Bicyclic azaheterocyclobenzylamines as PI3K inhibitors

ABSTRACT

The present invention provides bicyclic azaheterocyclobenzylamines of Formula I: 
                         
wherein the variables are defined herein, that modulate the activity of phosphoinositide 3-kinases (PI3Ks) and are useful in the treatment of diseases related to the activity of PI3Ks including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.

This application is a divisional of U.S. application Ser. No.13/854,789, filed Apr. 1, 2013, which claims the benefit of priority ofU.S. Provisional Application No. 61/619,210, filed Apr. 2, 2012, andU.S. Provisional Application No. 61/776,608, filed Mar. 11, 2013, thedisclosures of each of which are incorporated herein by reference intheir entireties.

FIELD OF THE INVENTION

The present invention provides bicyclic azaheterocyclobenzylaminederivatives, for example, pyrazolopyrimidines, that modulate theactivity of phosphoinositide 3-kinases (PI3Ks) and are useful in thetreatment of diseases related to the activity of PI3Ks including, forexample, inflammatory disorders, immune-based disorders, cancer, andother diseases.

BACKGROUND OF THE INVENTION

The phosphoinositide 3-kinases (PI3Ks) belong to a large family of lipidsignaling kinases that phosphorylate phosphoinositides at the D3position of the inositol ring (Cantley, Science, 2002,296(5573):1655-7). PI3Ks are divided into three classes (class I, II,and III) according to their structure, regulation and substratespecificity. Class I PI3Ks, which include PI3Kα, PI3KIβ, PI3Kγ, andPI3Kδ, are a family of dual specificity lipid and protein kinases thatcatalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate(PIP₂) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP₃).PIP₃ functions as a second messenger that controls a number of cellularprocesses, including growth, survival, adhesion and migration. All fourclass I PI3K isoforms exist as heterodimers composed of a catalyticsubunit (p110) and a tightly associated regulatory subunit that controlstheir expression, activation, and subcellular localization. PI3Kα,PI3KIβ, and PI3Kδ associate with a regulatory subunit known as p85 andare activated by growth factors and cytokines through a tyrosinekinase-dependent mechanism (Jimenez, et al., J Biol Chem., 2002,277(44):41556-62) whereas PI3Kγ associates with two regulatory subunits(p101 and p84) and its activation is driven by the activation ofG-protein-coupled receptors (Brock, et al., J Cell Biol., 2003,160(1):89-99). PI3Kα and PI3KIβ are ubiquitously expressed. In contrast,PI3Kγ and PI3Kδ are predominantly expressed in leukocytes(Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204).

The differential tissue distribution of the PI3K isoforms factors intheir distinct biological functions. Genetic ablation of either PI3Kα orPI3KIβ results in embryonic lethality, indicating that PI3Kα and PI3KIβhave essential and non-redundant functions, at least during development(Vanhaesebroeck, et al., 2005). In contrast, mice which lack PI3Kγ andPI3Kδ are viable, fertile and have a normal life span although they showan altered immune system. PI3Kγ deficiency leads to impaired recruitmentof macrophages and neutrophils to sites of inflammation as well asimpaired T cell activation (Sasaki, et al., Science, 2000,287(5455):1040-6). PI3Kγ-mutant mice have specific defects in B cellsignaling that lead to impaired B cell development and reduced antibodyresponses after antigen stimulation (Clayton, et al., J Exp Med. 2002,196(6):753-63; Jou, et al., Mol Cell Biol. 2002, 22(24):8580-91;Okkenhaug, et al., Science, 2002, 297(5583): 1031-4).

The phenotypes of the PI3Kγ and PI3Kγ-mutant mice suggest that theseenzymes may play a role in inflammation and other immune-based diseasesand this is borne out in preclinical models. PI3Kγ-mutant mice arelargely protected from disease in mouse models of rheumatoid arthritis(RA) and asthma (Camps, et al., Nat Med. 2005, 11(9):936-43; Thomas, etal., Eur J Immunol. 2005, 35(4):1283-91). In addition, treatment ofwild-type mice with a selective inhibitor of PI3Kγ was shown to reduceglomerulonephritis and prolong survival in the MRL-lpr model of systemiclupus nephritis (SLE) and to suppress joint inflammation and damage inmodels of RA (Barber, et al., Nat Med. 2005, 11(9):933-5; Camps, et al.,2005). Similarly, both PI3Kγ-mutant mice and wild-type mice treated witha selective inhibitor of PI3Kδ have been shown to have attenuatedallergic airway inflammation and hyper-responsiveness in a mouse modelof asthma (Ali, et al., Nature. 2004, 431(7011):1007-11; Lee, et al.,FASEB J. 2006, 20(3):455-65) and to have attenuated disease in a modelof RA (Randis, et al., Eur. J. Immunol., 2008, 38(5):1215-24).

B cell proliferation has shown to play a major role in the developmentof inflammatory autoimmune diseases (Puri, Frontiers in Immunology(2012), 3(256), 1-16; Walsh, Kidney International (2007) 72, 676-682).For example, B cells support T-cell autoreactivity, an importantcomponent of inflammatory autoimmune diseases. Once activated andmatured, B cells can traffic to sites of inflammation and recruitinflammatory cells or differentiate to plasmablasts. Thus, activity ofB-cells can be affected by targeting B-cell stimulatory cytokines,B-cell surface receptors, or via B-cell depletion. Rituximaban—IgG1 κmouse/human chimeric monoclonal antibody directed against the B-cellsurface receptor CD20—has been shown to deplete CD20+ B cells. Use ofrituximab has been shown to have efficacy in treating idiopathicthrombocytopenic purpura, autoimmune hemolytic anemia, or vasculitis.For example, treatment with rituximab resulted in remission of thedisease in patients suffering from anti-neutrophil cytoplasm antibodyassociated (ANCA) systemic vasculitis (AASV) with demonstratedperipheral B-cell depletion (Walsh, 2007; Lovric, Nephrol DialTransplant (2009) 24: 179-185). Similarly, a complete response wasreported in one-third to two-thirds of patients having mixedcryoglobulinemia vasculitis after treatment with rituximab, includingpatients who presented with a severe form of vasculitis that wasresistant or intolerant to other treatments (Cacoub, Ann Rheum Dis 2008;67:283-287). Similarly, rituximab has been shown to have efficacy intreating patients with idiopathic thrombocytopenic purpura (or immunethrombocytopenic purpura) (Garvey, British Journal of Haematology,(2008) 141, 149-169; Godeau, Blood (2008), 112(4), 999-1004; Medeo,European Journal of Haematology, (2008) 81, 165-169) and autoimmunehemolytic anemia (Garvey, British Journal of Haematology, (2008) 141,149-169).

PI3Kδ signaling has been tied to B cell survival, migration, andactivation (Puri, Frontiers in Immunology, 2012, 3(256), 1-16, at pages1-5; and Clayton, J Exp Med, 2002, 196(6):753-63). For example, PI3Kδ isrequired for antigen-dependent B-cell activation driven by B cellreceptor. By blocking B-cell adhesion, survival, activation, andproliferation, PI3Kδ inhibition can impair the ability of B cells toactivate T cells, preventing their activation and reducing secreation ofautoantibodies and pro-inflammatory cytokines. Hence, by their abilityto inhibit B cell activation, PI3Kδ inhibitors would be expected totreat B cell mediated diseases that were treatable by similar methodssuch as B cell depletion by rituximab. Indeed, PI3Kδ inhibitors havebeen shown to be useful mouse models of various autoimmune diseases thatare also treatable by rituximab such as arthritis (Puri (2012)).Further, innate-like B cells, which are linked to autoimmunity aresensitive to PI3Kδ activity, as MZ and B-1 cells are nearly absent inmice lacking the p110δ gene (Puri (2012). PI3Kδ inhibitors can reducetrafficking of and activation of MZ and B-1 cells, which are implicatedin autoimmune diseases.

In addition to their potential role in inflammatory diseases, all fourclass I PI3K isoforms may play a role in cancer. The gene encoding p110αis mutated frequently in common cancers, including breast, prostate,colon and endometrial (Samuels, et al., Science, 2004, 304(5670):554;Samuels, et al., Curr Opin Oncol. 2006, 18(1):77-82). Eighty percent ofthese mutations are represented by one of three amino acid substitutionsin the helical or kinase domains of the enzyme and lead to a significantupregulation of kinase activity resulting in oncogenic transformation incell culture and in animal models (Kang, et al., Proc Natl Acad Sci USA,2005, 102(3):802-7; Bader, et al., Proc Natl Acad Sci USA. 2006,103(5):1475-9). No such mutations have been identified in the other PI3Kisoforms although there is evidence that they can contribute to thedevelopment and progression of malignancies. Consistent overexpressionof PI31 δ is observed in acute myeloblastic leukemia (Sujobert, et al.,Blood, 2005, 106(3):1063-6) and inhibitors of PI3Kδ can prevent thegrowth of leukemic cells (Billottet, et al., Oncogene, 2006,25(50):6648-59). Elevated expression of PI3Kγ is seen in chronic myeloidleukemia (Hickey, et al., J Biol Chem. 2006, 281(5):2441-50).Alterations in expression of PI3KIβ, PI3Kγ and PI31 δ have also beenobserved in cancers of the brain, colon and bladder (Benistant, et al.,Oncogene, 2000, 19(44):5083-90; Mizoguchi, et al., Brain Pathol. 2004,14(4):372-7; Knobbe, et al., Neuropathol Appl Neurobiol. 2005,31(5):486-90). Further, these isoforms have all been shown to beoncogenic in cell culture (Kang, et al., 2006).

Thus, new or improved agents which inhibit kinases such as PI3K arecontinually needed for developing new and more effective pharmaceuticalsthat are aimed at augmentation or suppression of the immune andinflammatory pathways (such as immunosuppressive agents for organtransplants), as well as agents for the prevention and treatment ofautoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis,asthma, type I diabetes, inflammatory bowel disease, Crohn's disease,autoimmune thyroid disorders, Alzheimer's disease, nephritis), diseasesinvolving a hyperactive inflammatory response (e.g., eczema), allergies,lung diseases, cancer (e.g., prostate, breast, leukemia, multiplemyeloma), and some immune reactions (e.g., skin rash or contactdermatitis or diarrhea) caused by other therapeutics. The compounds,compositions, and methods described herein are directed toward theseneeds and others.

SUMMARY

The present invention provides, inter alia, a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables aredefined infra.

The present invention further provides compositions comprising acompound of the invention, or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier.

The present invention also provides methods of modulating an activity ofa PI3K kinase, comprising contacting the kinase with a compound of theinvention, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ina patient, wherein said disease is associated with abnormal expressionor activity of a PI3K kinase, comprising administering to said patient atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof.

The present invention further provides methods of treating animmune-based disease in a patient, comprising administering to saidpatient a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating a cancer in apatient, comprising administering to said patient a therapeuticallyeffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof.

The present invention further provides methods of treating a lungdisease in a patient, comprising administering to said patient atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof.

The present invention also provides a compound of the invention, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for use in any of the methods described herein.

DETAILED DESCRIPTION

The present invention provides, inter alia, a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

V is C(═O), S(═O)₂, CH₂, CHR^(3c), and CR^(3c)R^(3c);

T is C(═O), S(═O)₂, CH₂, CHR^(3a), and CR^(3a)R^(3a);

Q is C(═O), S(═O)₂, (CH₂)_(n), (CHR^(3a))_(n), and (CR^(3a)R^(3a))_(n);wherein n is 0, 1, or 2;

U is O or NR^(3d);

provided that when T is C(═O) or S(═O)₂, then Q is (CH₂)_(n),(CHR^(3a))_(n), or (CR^(3a)R^(3a))_(n);

further provided that when Q is C(═O) or S(═O)₂, then T is CH₂,CHR^(3a), or CR^(3a)R^(3a), and

U is NR^(3d);

R^(A) is H or alkyl;

Ar is

X¹ is CH or N;

Y¹ is CH or N;

or alternatively, R^(A) and Ar, together with the N to which they areattached, combine to form a moiety of formula:

X is CR⁹ or N;

W is CR⁷ or N;

Y is C⁸, CR^(8a), or N;

Z is a bond or C(═O);

provided that —W═Y—Z— is —CR⁷═CR⁸—, —N═CR⁸—, —CR⁷═CR^(8a)—C(═O)—,—N═CR^(8a)—C(═O)—, or —CR⁷═N—C(═O)—;

R¹ is alkyl;

each R^(3a) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and Cy¹; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, or3 independently selected R¹¹ groups;

R^(3b) is H, Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), S(═O)₂R^(b), orS(═O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(3c) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, and C₁₋₄ haloalkoxy-C₁₋₄ alkyl;

R^(3d) is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, or C₁₋₄haloalkoxy-C₁₋₄ alkyl;

R⁴ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁵ is halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, or cyclopropyl;

R⁶ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁷ is H or C₁₋₄ alkyl;

R⁸ is H, halo, —OH, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy², —(C₁₋₃ alkylene)-Cy², OR^(a2), SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2),NR^(2c)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2), NR^(c2)(═O)NR^(c2)R^(d2), (═NR^(e))R^(b2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(2c)R^(d2), NR^(c2)S(═O)R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)R^(b2), S(═O)₂R^(b2), orS(═O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted by 1, 2, 3, or 4 independently selectedR¹¹ groups;

R^(8a) is H, halo, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy², —(C₁₋₃ alkylene)-Cy², C(═O)R^(b2), C(═O)NR^(c2)R^(d2),C(═O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)R^(b2) S(═O)₂R^(b2), orS(═O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted by 1, 2, 3, or 4 independently selectedR¹¹ groups;

R⁹ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R¹⁰ is H or C₁₋₄ alkyl;

each R¹¹ is independently selected from halo, OH, NO₂, CN, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

each R^(13b) is independently selected from Cy¹, —(C₁₋₃ alkylene)-Cy¹,halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1),NR^(c1)S(═O)R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)R^(b1),S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

each Cy is independently selected from C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, phenyl, naphthyl, and 5-10 membered heteroaryl,wherein said C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, phenyl,naphthyl, and 5-10 membered heteroaryl are optionally substituted with1, 2, 3, or 4 independently selected R^(13b) groups;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 independently selected R^(13b) groups;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, or3 independently selected R^(13b) groups; or

alternatively, R^(c) and R^(d) together with the N atom to which theyare attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group,which is optionally substituted with 1, 2, or 3 independently selectedR^(13b) groups;

each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl, andC₁₋₄ alkoxy;

each Cy¹ is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein said C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl are optionally substituted with 1, 2, 3, or 4 independentlyselected R¹¹ groups;

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, or 3 independently selected R¹¹groups;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; or

alternatively, R^(c1) and R^(d1) together with the N atom to which theyare attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group,which is optionally substituted with —OH or C₁₋₃ alkyl;

each Cy² is independently selected from C₃₋₇cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, and 9-10-memberedbicyclic heteroaryl, each of which is optionally substituted with 1, 2,3, or 4 independently selected R¹¹ groups;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, or 3 independently selected R¹¹groups; and

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; or

alternatively, R^(c2) and R^(d2) together with the N atom to which theyare attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group,which is optionally substituted with —OH or C₁₋₃ alkyl.

The present invention further provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

V is C(═O), S(═O)₂, CH₂, CHR^(3c), and CR^(3c)R^(3c);

T is C(═O), S(═O)₂, CH₂, CHR^(3a), and CR^(3a)R^(3a);

Q is C(═O), S(═O)₂, (CH₂)_(n), (CHR^(3a))_(n), and (CR^(3a)R^(3a))_(n);wherein n is 0, 1, or 2;

U is O or NR^(3d);

provided that when T is C(═O) or S(═O)₂, then Q is (CH₂)_(n),(CHR^(3a))_(n), or (CR^(3a)R^(3a))_(n);

further provided that when Q is C(═O) or S(═O)₂, then T is CH₂,CHR^(3a), or CR^(3a)R^(3a), and U is NR^(3d);

R^(A) is H or C₁₋₃ alkyl;

Ar is

X¹ is CH or N;

Y¹ is CH or N;

or alternatively, R^(A) and Ar, together with the N to which they areattached, combine to form a moiety of formula:

X is CR⁹ or N;

W is CR⁷ or N;

Y is CR⁸, CR^(8a), or N;

Z is a bond or C(═O);

provided that —W═Y—Z— is —CR⁷═CR⁸—, —N═CR⁸—, —CR⁷═CR^(8a)—C(═O)—,—N═CR^(8a)—C(═O)—, or —CR⁷═N—C(═O)—;

R¹ is C₁₋₃ alkyl;

each R^(3a) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and Cy¹; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, or3 independently selected R¹¹ groups;

R^(3b) is H, Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), S(═O)₂R^(b), orS(═O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(3c) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, and C₁₋₄ haloalkoxy-C₁₋₄ alkyl;

R^(3d) is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, or C₁₋₄haloalkoxy-C₁₋₄ alkyl;

R⁴ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁵ is halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, or cyclopropyl;

R⁶ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁷ is H or C₁₋₄ alkyl;

R⁸ is H, halo, —OH, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy², —(C₁₋₃ alkylene)-Cy², OR^(a2), SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), C(═NR^(e))R^(b2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)S(═O)R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)R^(b2), S(═O)₂R^(b2), orS(═O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted by 1, 2, 3, or 4 independently selectedR¹¹ groups;

R^(8a) is H, halo, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy², —(C₁₋₃ alkylene)-Cy², C(═O)R^(b2), C(═O)NR^(c2)R^(d2),C(═O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)R^(b2), S(═O)₂R^(b2), orS(═O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylare each optionally substituted by 1, 2, 3, or 4 independently selectedR¹¹ groups;

R⁹ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R¹⁰ is H or C₁₋₄ alkyl;

each R¹¹ is independently selected from halo, OH, NO₂, CN, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

each R^(13b) is independently selected from Cy¹, —(C₁₋₃ alkylene)-Cy¹,halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1),NR^(c1)S(═O)R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)R^(b1),S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

each Cy is independently selected from C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, phenyl, naphthyl, and 5-10 membered heteroaryl,wherein said C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, phenyl,naphthyl, and 5-10 membered heteroaryl are optionally substituted with1, 2, 3, or 4 independently selected R^(13b) groups;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 independently selected R^(13b) groups;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, or3 independently selected R^(13b) groups; or

alternatively, R^(c) and R^(d) together with the N atom to which theyare attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group,which is optionally substituted with 1, 2, or 3 independently selectedR^(13b) groups;

each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl, andC₁₋₄ alkoxy;

each Cy¹ is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein said C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl are optionally substituted with 1, 2, 3, or 4 independentlyselected R¹¹ groups;

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, or 3 independently selected R¹¹groups;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; or

alternatively, R^(c1) and R^(d1) together with the N atom to which theyare attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group,which is optionally substituted with —OH or C₁₋₃ alkyl;

each Cy² is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, and 9-10-memberedbicyclic heteroaryl, each of which is optionally substituted with 1, 2,3, or 4 independently selected R¹¹ groups;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, or 3 independently selected R¹¹groups; and

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; or

alternatively, R^(c2) and R^(d2) together with the N atom to which theyare attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group,which is optionally substituted with —OH or C₁₋₃ alkyl.

In some embodiments, V is C(═O) or CH₂.

In some embodiments, V is C(═O).

In some embodiments, V is S(═O)₂.

In some embodiments, V is CHR^(3c).

In some embodiments, V is CH₂.

In some embodiments, T is CH₂.

In some embodiments, T is C(═O).

In some embodiments, T is S(═O)₂.

In some embodiments, T is CHR^(3a).

In some embodiments, T is CH(CH₃).

In some embodiments, Q is S(═O)₂.

In some embodiments, Q is (CHR^(3a))_(n); wherein n is 0, 1, or 2.

In some embodiments, Q is (CH₂)_(n); wherein n is 0, 1, or 2.

In some embodiments, Q is CH₂, CH(CH₃), CH(CH₂CH₃), or CH₂CH₂.

In some embodiments, n is 1.

In some embodiments, n is 0.

In some embodiments, Q is CHR^(3a).

In some embodiments, Q is CH₂.

In some embodiments, Q is CH(CH₃).

In some embodiments, Q is CH(CH₂CH₃).

In some embodiments, Q is CH₂CH₂.

In some embodiments, U is O.

In some embodiments, U is NR^(3d).

In some embodiments, U is NH.

In some embodiments, U is NCH₃.

In some embodiments, R^(A) is H; and Ar is

In some embodiments, R^(A) is H; and Ar is

In some embodiments, R^(A) is H; and Ar is

In some embodiments, R^(A) and Ar, together with the N to which they areattached, combine to form a moiety of formula:

In some embodiments, R^(A) and Ar, together with the N to which they areattached, combine to form a moiety of formula:

In some embodiments, R^(A) and Ar, together with the N to which they areattached, combine to form a moiety of formula:

In some embodiments, R^(A) and Ar, together with the N to which they areattached, combine to form a moiety of formula:

In some embodiments, R^(A) and Ar, together with the N to which they areattached, combine to form a moiety of formula:

In some embodiments, R^(A) and Ar, together with the N to which they areattached, combine to form a moiety of formula:

In some embodiments, R¹ is methyl.

In some embodiments, R¹ is methyl or ethyl.

In some embodiments, R⁴ is C₁₋₄ alkyl, halo, or CN.

In some embodiments, R⁴ is C₁₋₄ alkyl.

In some embodiments, R⁴ is methyl.

In some embodiments, R⁴ is halo.

In some embodiments, R⁴ is F.

In some embodiments, R⁴ is CN.

In some embodiments, R⁵ is halo.

In some embodiments, R⁵ is chloro.

In some embodiments, R⁶ is H.

In some embodiments, R^(3b) is H, Cy, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a), or S(═O)₂R^(b), wherein saidC₁₋₆ alkyl is optionally substituted by 1, 2, 3, or 4 independentlyselected R^(13b) groups.

In some embodiments, R^(3b) is H, Cy, C₁₋₆ alkyl, C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), or S(═O)₂R^(b), wherein said C₁₋₆ alkylis optionally substituted by 1, 2, 3, or 4 independently selectedR^(13b) groups;

each R^(a), R^(b), R^(c), and R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, and Cy; wherein said C₁₋₆ alkyl are eachoptionally substituted with 1, 2, or 3 independently selected R^(13b)groups.

In some embodiments, R^(3b) is H, Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a), orS(═O)₂R^(b), wherein said C₁₋₆ alkyl is optionally substituted by 1, 2,3, or 4 independently selected R^(13b) groups.

In some embodiments, R^(3b) is H, Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl,C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a), or S(═O)₂R^(b), wherein saidC₁₋₆ alkyl is optionally substituted by 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(a), R^(b), R^(c), and R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, and Cy; wherein said C₁₋₆ alkyl are eachoptionally substituted with 1, 2, or 3 independently selected R^(13b)groups.

In some embodiments, each Cy is independently selected from C₃₋₇cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, and 5-10 memberedheteroaryl, wherein said C₃₋₇ cycloalkyl, 4-8 membered heterocycloalkyl,phenyl, and 5-10 membered heteroaryl are optionally substituted with 1,2, 3, or 4 independently selected R^(13b) groups.

In some embodiments, each Cy is independently selected from monocyclicC₃₋₇ cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl, andmonocyclic 5-6 membered heteroaryl, wherein said monocyclic C₃₋₇cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl, andmonocyclic 5-6 membered heteroaryl are optionally substituted with 1, 2,3, or 4 independently selected R^(13b) groups.

In some embodiments, each R^(13b) is independently selected from CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a1), C(═O)R^(b1), or C(═O)OR^(a1).

In some embodiments, each R^(13b) is independently selected from CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1),C(═O)OR^(a1), NR^(c1)C(═O)R^(b1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹¹ groups.

In some embodiments, each R^(a1), R^(c1), and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and each R^(b1) isindependently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments, each R¹¹ is independently selected from OH, CN,C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃alkylcarbamyl, and di(C₁₋₃ alkyl)carbamyl.

In some embodiments, each R¹¹ is independently selected from OH andcarbamyl.

In some embodiments, the compound is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula III:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula IV, V is C(═O) or CH₂.

In some embodiments, the compound is a compound of Formula IVa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IVb:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula V, VI, VII,VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula XXI, XXII orXXIII:

or a pharmaceutically acceptable salt thereof.

In some embodiments, R^(a) is methyl or ethyl for the compound ofFormula XXI, XXII, or XIII, or pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula XXIa, XXIb,or XXIIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula XXIV:

or a pharmaceutically acceptable salt thereof.

In some embodiments, R^(3a) is methyl for the compound of Formula XXIV,or pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

V is C(═O), S(═O)₂, or CH₂;

T is C(═O), S(═O)₂, or CH₂;

Q is C(═O), S(═O)₂, or CH₂;

U is O or NR^(3d);

provided that when T is C(═O) or S(═O)₂, then Q is CH₂;

further provided that when Q is C(═O) or S(═O)₂, then T is CH₂, and U isNR^(3d);

R¹ is C₁₋₃ alkyl;

R^(3b) is H, Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are optionally substituted by 1, 2, 3, or 4independently selected R^(13b) groups;

R^(3d) is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, or C₁₋₄haloalkoxy-C₁₋₄ alkyl;

R⁴ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁵ is halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, or cyclopropyl;

R⁶ is H;

R⁸ is H, halo, —OH, —CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R¹⁰ is H or C₁₋₄ alkyl;

each R¹¹ is independently selected from halo, OH, NO₂, CN, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

each R^(13b) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)S(═O)R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(c1), S(═O)R^(b1),S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

each Cy is independently selected from C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, phenyl, and 5-10 membered heteroaryl, wherein saidC₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, and 5-10membered heteroaryl are optionally substituted with 1, 2, 3, or 4independently selected R^(13b) groups;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 independently selected R^(13b) groups;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, or3 independently selected R^(13b) groups; or

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, or 3 independently selected R¹¹groups; and

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; or

each Cy² is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, and 9-10-memberedbicyclic heteroaryl, each of which is optionally substituted with 1, 2,3, or 4 independently selected R¹¹ groups.

In some embodiments, the compound is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

V is C(═O), S(═O)₂, or CH₂;

T is C(═O), S(═O)₂, CH₂, or CH(CH₃);

Q is C(═O), S(═O)₂, CH₂, CH(CH₃), CH(CH₂CH₃), or CH₂CH₂;

U is O or NR^(3d);

provided that when T is C(═O) or S(═O)₂, then Q is CH₂ or CH(CH₃);

further provided that when Q is C(═O) or S(═O)₂, then T is CH₂, and U isNR^(3d);

R¹ is C₁₋₃ alkyl;

R^(3b) is H, Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are optionally substituted by 1, 2, 3, or 4independently selected R^(13b) groups;

R^(3d) is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, or C₁₋₄haloalkoxy-C₁₋₄ alkyl;

R⁴ is H, halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy;

R⁵ is halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, or cyclopropyl;

R⁶ is H;

R⁸ is H, halo, —OH, —CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R¹⁰ is H or C₁₋₄ alkyl;

each R¹¹ is independently selected from halo, OH, NO₂, CN, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,di(C₁₋₃ alkyl)amino, carbamyl, C₁₋₃ alkylcarbamyl, and di(C₁₋₃alkyl)carbamyl;

each R^(13b) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)S(═O)R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(c1), S(═O)R^(b1),S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

each Cy is independently selected from C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, phenyl, and 5-10 membered heteroaryl, wherein saidC₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, and 5-10membered heteroaryl are optionally substituted with 1, 2, 3, or 4independently selected R^(13b) groups;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 independently selected R^(13b) groups;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, or3 independently selected R^(13b) groups; or

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, or 3 independently selected R¹¹groups; and

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; or

each Cy² is independently selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, and 9-10-memberedbicyclic heteroaryl, each of which is optionally substituted with 1, 2,3, or 4 independently selected R¹¹ groups.

In some embodiments:

R⁴ is C₁₋₄ alkyl;

R⁵ is halo;

R⁶ is H;

R^(3b) is H, Cy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), or S(═O)₂R^(b), wherein said C₁₋₆ alkylis optionally substituted by 1, 2, 3, or 4 independently selectedR^(13b) groups;

each R^(a), R^(b), R^(c), and R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, and Cy; wherein said C₁₋₆ alkyl are eachoptionally substituted with 1, 2, or 3 independently selected R^(13b)groups;

each Cy is independently selected from monocyclic C₃₋₇ cycloalkyl,monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6membered heteroaryl, wherein said monocyclic C₃₋₇cycloalkyl, monocyclic4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 memberedheteroaryl are optionally substituted with 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(13b) is independently selected from CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a1), C(═O)R^(b1), and C(═O)OR^(a1);

each R^(a1) is independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl; and

each R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments:

R¹ is methyl;

R⁴ is methyl, F or CN;

R⁵ is Cl;

R⁶ is H;

R^(3b) is H, Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a), or S(═O)₂R^(b), wherein saidC₁₋₆ alkyl is optionally substituted by 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(a), R^(b), R^(c), and R^(d) is independently selected from C₁₋₆alkyl and Cy; wherein said C₁₋₆ alkyl is optionally substituted with 1,2, or 3 independently selected R^(13b) groups;

each Cy is independently selected from monocyclic C₃₋₇ cycloalkyl,monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6membered heteroaryl, wherein said monocyclic C₃₋₇ cycloalkyl, monocyclic4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 memberedheteroaryl are optionally substituted with 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(13b) is independently selected from CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),NR^(c1)C(═O)R^(b1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl is optionally substituted with 1 or 2 independently selectedR¹¹ groups;

each R¹¹ is independently selected from OH and carbamyl;

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, the compound is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R⁴ is C₁₋₄ alkyl;

R⁵ is halo;

R⁶ is H;

R¹⁰ is H or C₁₋₄ alkyl;

R^(3b) is H, Cy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), or S(═O)₂R^(b), wherein said C₁₋₆ alkylis optionally substituted by 1, 2, 3, or 4 independently selectedR^(13b) groups;

each R^(a), R^(b), R^(c), and R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, and Cy; wherein said C₁₋₆ alkyl are eachoptionally substituted with 1, 2, or 3 independently selected R^(13b)groups;

each Cy is independently selected from monocyclic C₃₋₇ cycloalkyl,monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6membered heteroaryl, wherein said monocyclic C₃₋₇ cycloalkyl, monocyclic4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 memberedheteroaryl are optionally substituted with 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(13b) is independently selected from CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a1), C(═O)R^(b1), and C(═O)OR^(a1);

each R^(a1) is independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl; and

each R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, the compound is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

V is C(═O) or CH₂;

R⁴ is C₁₋₄ alkyl;

R⁵ is halo;

R⁶ is H;

R⁸ is C₁₋₆ alkyl;

R¹⁰ is H or C₁₋₄ alkyl;

R^(3b) is H, Cy, C₁₋₆ alkyl, C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a),or S(═O)₂R^(b), wherein said C₁₋₆ alkyl is optionally substituted by 1,2, 3, or 4 independently selected R^(13b) groups;

each R^(a), R^(b), R^(c), and R^(d) is independently selected from C₁₋₆alkyl and Cy; wherein said C₁₋₆ alkyl are each optionally substitutedwith 1, 2, or 3 independently selected R^(13b) groups;

each Cy is independently selected from monocyclic C₃₋₇ cycloalkyl,monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6membered heteroaryl, wherein said monocyclic C₃₋₇ cycloalkyl, monocyclic4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 memberedheteroaryl are optionally substituted with 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(13b) is independently selected from CN, C₁₋₆ alkyl, OR^(a1),C(═O)R^(b1), and C(═O)OR^(a1);

each R^(a1) is independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl; and

each R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, the compound is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

V is C(═O) or CH₂;

R¹ is methyl;

R⁴ is methyl, F or CN;

R⁵ is Cl;

R⁶ is H;

R^(3b) is H, Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a), or S(═O)₂R^(b), wherein saidC₁₋₆ alkyl is optionally substituted by 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(a), R^(b), R^(c), and R^(d) is independently selected from C₁₋₆alkyl and Cy; wherein said C₁₋₆ alkyl is optionally substituted with 1,2, or 3 independently selected R^(13b) groups; each Cy is independentlyselected from monocyclic C₃₋₇ cycloalkyl, monocyclic 4-7 memberedheterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl,wherein said monocyclic C₃₋₇ cycloalkyl, monocyclic 4-7 memberedheterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl areoptionally substituted with 1, 2, 3, or 4 independently selected R^(13b)groups;

each R^(13b) is independently selected from CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),NR^(c1)C(═O)R^(b1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(c1), wherein saidC₁₋₆ alkyl is optionally substituted with 1 or 2 independently selectedR¹¹ groups;

each R¹¹ is independently selected from OH and carbamyl;

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, the compound is a compound of Formula XXI, XXII, orXXXIII:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is methyl;

R^(3a) is methyl or ethyl;

R⁴ is methyl, F or CN;

R⁵ is Cl;

R⁶ is H;

R^(3b) is H, Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a), or S(═O)₂R^(b), wherein saidC₁₋₆ alkyl is optionally substituted by 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(a), R^(b), R^(c), and R^(d) is independently selected from C₁₋₆alkyl and Cy; wherein said C₁₋₆ alkyl is optionally substituted with 1,2, or 3 independently selected R^(13b) groups;

each Cy is independently selected from monocyclic C₃₋₇ cycloalkyl,monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6membered heteroaryl, wherein said monocyclic C₃₋₇ cycloalkyl, monocyclic4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 memberedheteroaryl are optionally substituted with 1, 2, 3, or 4 independentlyselected R^(13b) groups;

each R^(13b) is independently selected from CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),NR^(c1)C(═O)R^(b1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl is optionally substituted with 1 or 2 independently selectedR¹¹ groups;

each R¹¹ is independently selected from OH and carbamyl;

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, the compound is a compound of Formula XXIV:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is methyl;    -   R^(3a) is methyl;    -   R⁴ is methyl, F or CN;    -   R⁵ is Cl;    -   R⁶ is H;    -   R^(3b) is H, Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a), or        S(═O)₂R^(b), wherein said C₁₋₆ alkyl is optionally substituted        by 1, 2, 3, or 4 independently selected R^(13b) groups;    -   each R^(a), R^(b), R^(c), and R^(d) is independently selected        from C₁₋₆ alkyl and Cy; wherein said C₁₋₆ alkyl is optionally        substituted with 1, 2, or 3 independently selected R^(13b)        groups;    -   each Cy is independently selected from monocyclic C₃₋₇        cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl,        and monocyclic 5-6 membered heteroaryl, wherein said monocyclic        C₃₋₇ cycloalkyl, monocyclic 4-7 membered heterocycloalkyl,        phenyl, and monocyclic 5-6 membered heteroaryl are optionally        substituted with 1, 2, 3, or 4 independently selected R^(13b)        groups;    -   each R^(13b) is independently selected from CN, C₁₋₆ alkyl, C₁₋₆        haloalkyl, OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1),        C(═O)OR^(a1), NR^(c1)C(═O)R^(b1), S(═O)₂R^(b1), and        S(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl is optionally        substituted with 1 or 2 independently selected R¹¹ groups;    -   each R¹¹ is independently selected from OH and carbamyl;    -   each R^(a1), R^(c1), and R^(d1) is independently selected from        H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and    -   each R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆        haloalkyl.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment (the embodiments in thespecification should be construed as if they were written as claims,which are multiply dependent on each of the other embodiments).Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is to beunderstood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.Examples of alkyl moieties include, but are not limited to, chemicalgroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl,3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. In someembodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms. Example alkenyl groups include, but are not limited to,ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “alkylene”, employed alone or in combinationwith other terms, refers to a divalent alkyl linking group. Examples ofalkylene groups include, but are not limited to, ethan-1,2-diyl,propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl,butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy),t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6,1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms.

In some embodiments, each alkyl group has, independently, 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(═O)— group. Also may be written asC(O).

As used herein, the term “cyano-C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-OH.

As used herein, the term “C₁₋₃ alkoxy-C₁₋₃ alkyl” refers to a group offormula —(C₁₋₃ alkylene)-O(C₁₋₃ alkyl).

As used herein, the term “C₁₋₄ alkoxy-C₁₋₄ alkyl” refers to a group offormula —(C₁₋₄ alkylene)-O(C₁₋₄ alkyl).

As used herein, the term “C₁₋₄ haloalkoxy-C₁₋₄ alkyl” refers to a groupof formula —(C₁₋₄ alkylene)-O(C₁₋₄ haloalkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments,the halo group is F or Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. In some embodiments, the haloalkoxy group is fluorinated only. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groupsand spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, or 7ring-forming carbons (C₃₋₇). Ring-forming carbon atoms of a cycloalkylgroup can be optionally substituted by oxo or sulfido. Cycloalkyl groupsalso include cycloalkylidenes. Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, and the like. In some embodiments,cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Alsoincluded in the definition of cycloalkyl are moieties that have one ormore aromatic rings fused (i.e., having a bond in common with) to thecycloalkyl ring, for example, benzo or thienyl derivatives ofcyclopentane, cyclohexane, and the like. A cycloalkyl group containing afused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring.

As used herein, “heteroaryl” refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen, and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring.

A five-membered heteroaryl ring is a heteroaryl with a ring having fivering atoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, and S. Exemplary five-membered ringheteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl with a ring having sixring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, and S. Exemplary six-membered ringheteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl andpyridazinyl.

A “bicyclic C₉₋₁₀ heteroaryl” is bicyclic fused heteroaryl having 9 to10 ring members.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic orpolycyclic heterocycles having one or more ring-forming heteroatomsselected from O, N, or S. Included in heterocycloalkyl are monocyclic4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkylgroups can also include spirocycles. Example heterocycloalkyl groupsinclude pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl,tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, andthe like. Ring-forming carbon atoms and heteroatoms of aheterocycloalkyl group can be optionally substituted by oxo or sulfido(e.g., C(O), S(O), C(S), or S(O)₂, etc.). The heterocycloalkyl group canbe attached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo or thienyl derivatives of piperidine, morpholine,azepine, etc. A heterocycloalkyl group containing a fused aromatic ringcan be attached through any ring-forming atom including a ring-formingatom of the fused aromatic ring. In some embodiments, theheterocycloalkyl has 4-10, 4-7 or 4-6 ring atoms with 1 or 2 heteroatomsindependently selected from nitrogen, oxygen or sulfur and having one ormore oxidized ring members.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

In some embodiments, the compound has the (R)-configuration (e.g., atthe carbon to which R¹ is attached). In some embodiments, the compoundhas the (S)-configuration (e.g., at the carbon to which R¹ is attached).

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature” or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (ACN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999), which is incorporated herein by referencein its entirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

In the Schemes below, the enantiomers of the compounds of Formula (I)(e.g., the carbon to which R¹ is attached is a chiral carbon) can beseparated by chiral chromatography to afford a single enantiomer.Alternatively, a chiral intermediate may be separate by chiralchromatography and then used in the remaining steps of the Scheme toform a compound of Formula (I).

Compounds of Formula I can be formed as shown in Scheme I. Compound (i)can be acylated with a suitable acylating reagent (e.g., R¹—COCl) toform an ester which can be rearranged under Lewis acid conditions (e.g.,BF₃/HOAc complex) to afford ketone (ii). Halogenation of ketone (ii)using NX²S (e.g., NX²S=N-chlorosuccinamide, N-bromosuccinamide orN-iodosuccinamide) can give compound (iii) where X²=Cl, Br, or I. Thephenol can be converted to the ether (v) using standard Mitsunobuconditions (e.g., R″OH, where R″OH=HO-Q-T-NR^(3b), for exampleHOCH₂CH₂NR^(3b)P, where P is a protecting group, such as Boc or Cbz, andactivating agents, such as DEAD, Ph₃P;) or standard alkylatingconditions (base and R″-Lg, where Lg=leaving group; for example Na₂CO₃and BrCH₂CH₂NHP, where P is a protecting group, such as Boc or Cbz). Thehalo group of (v) can be coupled to a vinyl boronic acid or vinylboronic ester (vi) (R^(3c)-M, where M is a boronic acid, boronic esteror an appropriately substituted metal (e.g., R^(3c)-M is R^(3c)—B(OH)₂,R^(3c)—Sn(Bu)₄, or Zn—R^(3c)), under standard Suzuki conditions orstandard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a vinyl derivative(vii). Oxidation of the vinyl group of compound (vii) under standardconditions (e.g., OsO₄ and then NaIO₄ or ozone and then a reducingagent, such as triphenylphosphine or DMS, can provide compound (viii).Deprotection of the nitrogen protecting group can give the amine thatcan cyclize to form the imine and be reduced with a suitable reagent,such as NaBH₄, to give an alcohol which can be converted to anintermediate (ix) bearing a leaving group, (e.g., Lg is chloride viareaction with SO₂Cl₂ or cyanuric chloride or mesylate via reaction withmethanesulfonic anhydride). The intermediate (ix) can be reacted with aheterocycle (x) in the presence of a base (e.g., CsCO₃ or NaH) to give aheterocyclic derivative (xi). Alternatively, the intermediate (ix) canbe converted to an azide derivative which can be reduced to an amine(xii) under appropriate reducing conditions, such as trimethylphosphineor TMSI. The amine (xii) can be optionally reacted with an appropriatealkylating agent R^(A)X (e.g., MeI) or reacted under reductive aminationconditions to give a secondary amine which can be reacted with aheteroaryl halide compound (e.g., Ar—X, such as 6-chloro-9H-purine) togive a compound of Formula I (xiii). The reaction of amine (xii) withR^(A)—X³ can be skipped to give compounds of Formula I (xiii), whereinR^(A) is H.

Compounds of Formula I can be formed as shown in Scheme II. Carbonylderivative (i) (compound viii from Scheme I where R^(3b)=H) can beN-deprotected to give an amine that can cyclize to form an imine andthen be reduced with a suitable reagent, such as NaBH₄, to give abicyclic alcohol containing compound (ii). The alcohol (ii) which can beconverted to a derivative bearing a leaving group, (e.g., Lg is chloridevia reaction with SO₂Cl₂ or cyanuric chloride or mesylate via reactionwith methanesulfonic anhydride) and then reacted with a heterocycle(iii) in the presence of a base (e.g., CsCO₃ or NaH) to give aheterocyclic derivative (iv). N-deprotection and reaction with a varietyof acylating or alkylating or arylating agents can provide compounds(v). Alternatively, ketone (i) (compound (viii) from Scheme I whereR^(3b)=H) can be N-deprotected to give an amine that can cyclize to forman imine and then be reduced with a suitable reagent, such as NaCNBH₃ togive a bicyclic amine (vi). Reaction of the amine (vi) with a variety ofacylating or alkylating or arylating agents and then reduction of theketone and conversion of the alcohol to a derivative bearing a leavinggroup, (e.g., Lg is chloride via reaction with SO₂Cl₂ or cyanuricchloride or mesylate via reaction with methanesulfonic anhydride) canprovide compounds (vii). Reaction with a heterocycle (iii) in thepresence of a base (e.g., CsCO₃ or NaH) can give a bicyclic derivative(v). Alternatively, intermediate (vii) can be converted to an azide andreduced with a suitable agent, such as trimethylphosphine or TMSI. Theamine (viii) can be optionally reacted with an appropriate alkylatingagent R^(A)X³ (e.g., MeI) or reacted under reductive aminationconditions to give a secondary amine which can be reacted with aheteroaryl halide compound (e.g., Ar—X⁴, such as 6-chloro-9H-purine) togive a compound of Formula I (ix). The reaction of amine (viii) withR^(A)—X³ can be skipped to give compounds of Formula I (ix), whereinR^(A) is H.

Compounds of Formula I can be formed as shown in Scheme III. Aldehyde(i) (compound viii from Scheme I) can be oxidized to the correspondingcarboxylic acid and then N-deprotected to give an amine that can cyclizeunder standard peptide coupling conditions (e.g., HATU with DIEA) toprovide an amide (ii). Alternatively, when R^(3b)=H, the amine of thecarboxylic acid can be N-deprotected and converted to a secondary amineunder reductive amination conditions or alkylation (e.g., NaCNBH₃ andR^(3b)CHO or R^(3b)-halo and base) and then cyclized under standardpeptide coupling conditions (e.g., HATU with DIEA) to provide an amide(ii). The ketone of compound (ii) can be converted to compounds ofFormula I (iv and vi) by similar methods as described in Schemes I andII.

Compounds of Formula I can be formed as shown in Scheme IV. Phenol (i)can be converted to the corresponding triflate (ii) using triflicanhydride and base and then coupled to an amine (iv) by heating in baseor under Buchwald conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., an alkoxide base)) to afford diamine (iii). Halogenation ofdiamine (iii) using NX²S (e.g., NX²S=N-chlorosuccinamide,N-bromosuccinamide or N-iodosuccinamide) can give compound (v) whereX²=Cl, Br, or I. The halo group of (v) can be coupled to a vinyl boronicacid or vinyl boronic ester (vi) (R^(3c)-M, where M is a boronic acid,boronic ester or an appropriately substituted metal (e.g., R^(3c)-M isR^(3c)—B(OH)₂, R^(3c)—Sn(Bu)₄, or Zn—R^(3c)), under standard Suzukiconditions or standard Stille conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., a bicarbonate or carbonate base) or standard Negishiconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a vinyl derivative(vii). Oxidation of the vinyl group of compound (vii) under standardconditions (e.g., OsO₄ and then NaIO₄ or ozone and then a reducingagent, such as triphenylphosphine or DMS) can provide compound (viii).Deprotection of the nitrogen protecting group can give the amine thatcan cyclize to form the imine and be reduced with a suitable reagent,such as NaBH₄, to give an alcohol that can be converted to aintermediate (ix) bearing a leaving group, (e.g., Lg is chloride viareaction with SO₂Cl₂ or cyanuric chloride or mesylate via reaction withmethanesulfonic anhydride). Intermediate (ix) can be converted tocompounds of Formula I (xi and xiii) by similar methods as described inSchemes I and II.

Compounds of Formula I can be formed as shown in Scheme V. Aldehyde (i)(compound viii where R^(3c)=H in Scheme IV) can be oxidized to thecorresponding carboxylic acid and then N-deprotected to give an aminethat can cyclize under standard peptide coupling conditions (e.g., HATUwith DIEA) to provide an amide and then be reduced with a suitablereagent, such as NaBH₄, and the resulting alcohol can be converted to aintermediate (ii) bearing a leaving group, (e.g., Lg is chloride viareaction of the alcohol with SO₂Cl₂ or cyanuric chloride or mesylate viareaction with methanesulfonic anhydride). The intermediate compound (ii)can be converted to compounds of Formula I (iv and vi) by similarmethods as shown for intermediates bearing leaving groups in Schemes Iand II.

Compounds of Formula I can be formed as shown in Scheme VI. Phenol (i)can be converted to the corresponding triflate (ii) using triflicanhydride and base and then coupled to an amino-ester (e.g., R² isalkyl) (iv) by heating in base or under Buchwald conditions (e.g., inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to afford ester (iii). Halogenation of ketone (iii) using NX²S(e.g., NX²S=N-chlorosuccinamide, N-bromosuccinamide orN-iodosuccinamide) can give compound (v) where X²=Cl, Br, or I. The halogroup of (v) can be coupled to a vinyl boronic acid or vinyl boronicester (vi) (R^(3c)-M, where M is a boronic acid, boronic ester or anappropriately substituted metal (e.g., R^(3c)-M is R^(3c)—B(OH)₂,R^(3c)—Sn(Bu)₄, or Zn—R^(3c)), under standard Suzuki conditions orstandard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a vinyl derivative(vii). Oxidation of the vinyl group of compound (vii) under standardconditions (e.g., OsO₄ and then NaIO₄ or ozone and then a reducingagent, such as triphenylphosphine or DMS, can provide compound (viii).Reductive amination with a suitable amine (R^(3b)NH₂) and appropriatereducing agent (e.g., NaCHBH₃) can give the corresponding amine productthat can intramolecularly cyclize to form the amide and then be reducedwith a suitable reagent, such as NaBH₄, and the resulting alcohol can beconverted to a intermediate (ix) bearing a leaving group, (e.g., Lg ischloride via reaction with SO₂Cl₂ or cyanuric chloride or mesylate viareaction with methanesulfonic anhydride). Intermediate (ix) can beconverted to compounds of Formula I (xi and xiii) by similar methods asdescribed in Schemes I and II.

Compounds of Formula I can be formed as shown in Scheme VII. Phenol (i)can be converted to the corresponding triflate (ii) using triflicanhydride and base and then coupled to a primary amine (R^(3d)NH₂) byheating in base or under Buchwald conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., an alkoxide base)), and then peptide coupling to anamino-acid (iv) can afford amide (iii). Halogenation of amide (iii)using NX²S (e.g., NX²S=N-chlorosuccinamide, N-bromosuccinamide orN-iodosuccinamide) can give compound (v) where X²=Cl, Br, or I. The halogroup of (v) can be coupled to a vinyl boronic acid or vinyl boronicester (vi) (R^(3c)-M, where M is a boronic acid, boronic ester or anappropriately substituted metal (e.g., R^(3c)-M is R^(3c)—B(OH)₂,R^(3c)—Sn(Bu)₄, or Zn—R^(3c)), under standard Suzuki conditions orstandard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a vinyl derivative(vii). Oxidation of the vinyl group of compound (vii) under standardconditions (e.g., OsO₄ and then NaIO₄ or ozone and then a reducingagent, such as triphenylphosphine or DMS, can provide compound (viii).Deprotection of the nitrogen protecting group can give the amine thatcan cyclize to form the imine and be reduced with a suitable reagent,such as NaBH₄, to give bicyclic alcohol which can be converted to aderivative (ix) bearing a leaving group, (e.g., Lg is chloride viareaction with SO₂Cl₂ or cyanuric chloride or mesylate via reaction withmethanesulfonic anhydride). Intermediate (ix) can be converted tocompounds of Formula I (xi and xiii) by similar methods as described inSchemes I, II and III.

Compounds of Formula I can be formed as shown in Scheme VIII.Halogenation of ketone (i) using NX¹S (e.g., NX¹S=N-chlorosuccinamide,N-bromosuccinamide or N-iodosuccinamide) can give compound (ii) whereX¹=Cl, Br, or I. The phenol can be reacted with a halo-ester (iii) togive the ether (iv) using standard alkylating conditions (Base andR′-Lg, where Lg=leaving group (e.g., NaH and BrCR^(3a)CO₂Me). The halogroup of (iv) can be coupled to a vinyl boronic acid or vinyl boronicester (v) (R^(3c)-M, where M is a boronic acid, boronic ester or anappropriately substituted metal (e.g., R^(3c)-M is R^(3c)—B(OH)₂,R^(3c)—Sn(Bu)₄, or Zn—R^(3c)), under standard Suzuki conditions orstandard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a vinyl derivative(vi). Oxidation of the vinyl group of compound (vi) under standardconditions (e.g., OsO₄ and then NaIO₄ or ozone and then a reducingagent, such as triphenylphosphine or DMS, can provide compound (vii).Reductive amination with a suitable amine (R^(3b)NH₂) and appropriatereducing agent (e.g., NaCNBH₃) can give the corresponding amine productthat can intramolecularly cyclize to form the amide and then be reducedwith a suitable reagent, such as NaBH₄, and the resulting alcohol can beconverted to a derivative (viii) bearing a leaving group, (e.g., Lg ischloride via reaction with SO₂Cl₂ or cyanuric chloride or mesylate viareaction with methanesulfonic anhydride). Intermediate (viii) can beconverted to compounds of Formula I (x and xii) by similar methods asdescribed in Schemes I and II.

Compounds of Formula I can be formed as shown in Scheme IX. Aldehyde (i)(compound vii where R^(3c)=H in Scheme VIII) can be oxidized to thecorresponding carboxylic acid and then N-deprotected to give an aminethat can cyclize under standard peptide coupling conditions (e.g., HATUwith DIEA) to provide an amide and then be reduced with a suitablereagent, such as NaBH₄, and the resulting alcohol can be converted to anintermediate (ii) bearing a leaving group, (e.g., Lg is chloride viareaction of the alcohol with SO₂Cl₂ or cyanuric chloride or mesylate viareaction with methanesulfonic anhydride). The intermediate compound (ii)can be converted to compounds of Formula I (iv and vi) by similarmethods as shown for intermediates bearing leaving groups in Schemes Iand II.

Compounds of Formula I can be formed as shown in Scheme X. Phenol (i)can be converted to the corresponding triflate (ii) using triflicanhydride and base and then coupled to a primary amine (e.g., R^(3b)NH₂)by heating in base or under Buchwald conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) and further protection (e.g., Boc or Cbz using (Boc)₂O or Cbz-Cl,respectively) of the resulting amine can give compound (iii).Halogenation of compound (iii) using NX²S (e.g.,NX²S=N-chlorosuccinamide, N-bromosuccinamide or N-iodosuccinamide) cangive compound (v) where X²=Cl, Br, or I. The halo group of (v) can becoupled to a vinyl boronic acid or vinyl boronic ester (vi) (R^(3c)-M,where M is a boronic acid, boronic ester or an appropriately substitutedmetal (e.g., R^(3c)-M is R^(3c)—B(OH)₂, R^(3c)—Sn(Bu)₄, or Zn—R^(3c)),under standard Suzuki conditions or standard Stille conditions (e.g., inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a vinyl derivative(vii). Oxidation of the vinyl group of compound (vii) under standardconditions (e.g., OsO₄ and then NaIO₄ or ozone and then a reducingagent, such as triphenylphosphine or DMS, can provide compound (viii).Reductive amination of carbonyl derivative (viii) with a suitable amine(iv) (e.g., R^(3b)NH₂) and appropriate reducing agent (e.g., NaCHBH₃)can give the corresponding amine product. Deprotection of the nitrogenprotecting group can give a diamine that can be cyclized to form a urea(e.g., Q=CO by reaction with phosgene) or sulfamide (e.g., Q=SO₂ byreaction with SO₂Cl₂ or NH₂SO₂NH₂) and then reduction with a suitablereagent, such as NaBH₄, can give an alcohol which can be furtherconverted to an intermediate (ix) bearing a leaving group, (e.g., Lg ischloride via reaction with SO₂Cl₂ or cyanuric chloride or mesylate viareaction with methanesulfonic anhydride). The intermediate compound (ix)can be converted to compounds of Formula I (xi and xiii) by similarmethods as shown for intermediates bearing leaving groups in Schemes Iand II.

Compounds of Formula I can be formed as shown in Scheme XI. Phenol (i)can reacted with a suitable reagent (e.g., H₂SO₄) to form a sulfatewhich can be chlorinated using standard conditions (e.g., SOCl₂) toafford a sulfonylchloride (ii). Reaction of the sulfonylchoride with anamine (iv) can give a sulfonamide (iii). When the amine (iv) contains asecond amino group (U ═NPR^(2d)) the sulfonamide (ii) can be reactedwith triflic anhydride to give a triflate and then the amine deprotectedand cyclized by heating in the presence of base or under Buchwaldconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to give the bicyclic compound (vi). The carbonyl of compound (vi)can be reduced with a suitable reagent, such as NaBH₄, to give analcohol which can be further converted to an intermediate (vii) bearinga leaving group, (e.g., Lg is chloride via reaction with SO₂Cl₂ orcyanuric chloride or mesylate via reaction with methanesulfonicanhydride). The intermediate compound (vii) can be converted tocompounds of Formula I by similar methods as shown for intermediatesbearing leaving groups in Schemes I and II. Alternatively, when theamine (iv) contains an alcohol group (U═OH) the sulfonamide (viii) canbe intramolecularly cyclized to an ether (ix) using standard Mitsunobuconditions (e.g., DEAD, Ph₃P). The ketone of compound (ix) can bereduced with a suitable reagent, such as NaBH₄, to give an alcohol whichcan be further converted to an intermediate (x) bearing a leaving group,(e.g., Lg is chloride via reaction with SO₂Cl₂ or cyanuric chloride ormesylate via reaction with methanesulfonic anhydride). The intermediatecompound (x) can be converted to compounds of Formula I by similarmethods as shown for intermediates bearing leaving groups in Schemes Iand II.

Compounds of Formula I can be formed as shown in Scheme XII. Carbonylderivative (i) can be reductively aminated with an amine (e.g.,NH₂R^(3b) in the presence of NaCNBH₃) and then reacted with asulfonylchloride (e.g., ClSO₂QCl, where Q=(CR^(3a)R^(3a))_(n)) to givethe corresponding sulfonamide (ii). Deprotection of the nitrogen andsubsequent cyclization followed by reduction of the carbonyl with asuitable reagent, such as NaBH₄, can give an alcohol which can befurther converted to an intermediate (iii) bearing a leaving group,(e.g., Lg is chloride via reaction with SO₂Cl₂ or cyanuric chloride ormesylate via reaction with methanesulfonic anhydride). The intermediatecompound (iii) can be converted to compounds of Formula I by similarmethods as shown for intermediates bearing leaving groups in Schemes Iand II. Alternatively, the amine of compound (i) can be deprotected andreacted with a sulfonylchloride (e.g., ClSO₂QCl, whereQ=(CR^(3a)R^(3a))_(n)) to give the corresponding sulfonamide (iv).Reductive amination of the sulfonamide (iv) with an amine (e.g.,NH₂R^(3b) in the presence of a reducing agent, such as NaCNBH₃) followedby intramolecular cyclization and subsequent reduction with a suitablereagent, such as NaBH₄, to give an alcohol which can be furtherconverted to an intermediate (v) bearing a leaving group, (e.g., Lg ischloride via reaction with SO₂Cl₂ or cyanuric chloride or mesylate viareaction with methanesulfonic anhydride). The intermediate compound (v)can be converted to compounds of Formula I by similar methods as shownfor intermediates bearing leaving groups in Schemes I and II.

Compound of Formula I can be synthesized from an acid chloride compound(i) as illustrated in Scheme XIII. Condensation of an acid chloride (i)with malononitrile in the presence of a base, such as sodium hydride,can give a dicyanoenol intermediate, which can be O-methylated with anappropriate reagent, such as dimethyl sulfate in the presence of anappropriate base, such as sodium bicarbonate, to yield an enol ether(ii). Reaction of enol ether (ii) with hydrazine dihydrochloride in thepresence of a suitable base, such as triethylamine, can give a pyrazolecompound (iii). Pyrazole compound (iii) can then be reacted withformamide to give pyrazolopyrimidine (iv). Finally, compound (iv) can bereacted with appropriate compound bearing a leaving group (v) underbasic conditions to give a compound of Formula I (vi).

Compounds of Formula I can also be formed as shown in Scheme XIV. Thecompound (i) can be reacted with a halo-substituted heterocycle (ii)(e.g., 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine or4-amino-6-iodopyrido[2,3-d]pyrimidin-5 (8H)-one) under basic conditions(e.g., NaH or CsCO₃ or K₂CO₃) to give compound (iii) where X²=Cl, Br, orI. The halo group of (iii) can be coupled to R³-M, where M is a boronicacid, boronic ester or an appropriately substituted metal (e.g., R⁸-M isR⁸—B(OH)₂, R⁸—Sn(Bu)₄, or Zn—R⁸), under standard Suzuki conditions orstandard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative offormula (iii). Alternatively, R⁸-M can be a cyclic amine (where M is Hand attached to the amine nitrogen) with coupling to compound (iii)being performed by heating in base or under Buchwald conditions (e.g.,in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to afford compounds of Formula I (iv).

Compounds of Formula I can be synthesized from commercially available4-aminopyrido[2,3-d]pyrimidine-5(8H)-one (i) as shown in Scheme XV.Halogenation of compound (i) with suitable reagents, such as N-halosuccinamide (NX²S, where X²=Cl, Br or I) can give the corresponding halocompound (ii). Reaction of the halo derivative (ii) with a compound(iii) bearing a leaving group in the presence of a suitable base (e.g.diisopropylethylamine) can give compound (iv). The halo compound (iv)can be coupled to R^(8a)-M, where M is a boronic acid, boronic ester oran appropriately substituted metal (e.g., R^(8a)-M is R^(8a)—B(OH)₂,R^(8a)—Sn(Bu)₄, or Zn—R^(8a)), under standard Suzuki conditions orstandard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative offormula (iii). Alternatively, R^(8a)-M can be a cyclic amine (where M isH and attached to the amine nitrogen) with coupling to compound (iii)being performed by heating in base or under Buchwald conditions (e.g.,in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to afford compounds of Formula I (v).

Compounds of Formula I can also be formed as shown in Scheme XVI. Thecompound (i) can be reacted with a halo-substituted heterocycle (ii)(e.g., 6-chloro-9H-purine) under basic conditions (e.g., NaH or CsCO₃ orK₂CO₃) to give a compound of Formula I (ii).

Ketones which can be used in the processes of Scheme I, II and III, canalso be formed as shown in Scheme XVII. The carboxylic acid (i) can beactivated with a coupling agent (e.g. HBTU or HATU) and then reactedwith N, O-dimethylhydroxylamine to give a N-methoxy-N-methylcarboxamide.Reaction of compound (ii) with a Grignard reagent of formula R¹—MgX²(X²=halo) can give ketone (iii). The ketone (iii) can be transformedusing similar methods as shown in Scheme I, II and III to affordcompounds of Formula I.

Compounds of Formula I can also be formed as shown in Scheme XVIII. Thecompound (i) can be reacted with a halo-substituted heterocycle (ii)(e.g., 4-chloropyrido[3,2-d]pyrimidine [Anichem, cat #: N10204] and7-chlorothiazolo[5,4-d]pyrimidine) [Combi-Blocks, cat #: QA2711] underbasic conditions (e.g., NaH or CsCO₃ or K₂CO₃) to give a compound ofFormula I (ii).

Methods

The compounds of the invention can modulate activity of one or more ofvarious kinases including, for example, phosphoinositide 3-kinases(PI3Ks). The term “modulate” is meant to refer to an ability to increaseor decrease the activity of one or more members of the PI3K family.Accordingly, the compounds of the invention can be used in methods ofmodulating a PI3K by contacting the PI3K with any one or more of thecompounds or compositions described herein. In some embodiments,compounds of the present invention can act as inhibitors of one or morePI3Ks. In further embodiments, the compounds of the invention can beused to modulate activity of a PI3K in an individual in need ofmodulation of the receptor by administering a modulating amount of acompound of the invention, or a pharmaceutically acceptable saltthereof. In some embodiments, modulating is inhibiting.

Given that cancer cell growth and survival is impacted by multiplesignaling pathways, the present invention is useful for treating diseasestates characterized by drug resistant kinase mutants. In addition,different kinase inhibitors, exhibiting different preferences in thekinases which they modulate the activities of, may be used incombination. This approach could prove highly efficient in treatingdisease states by targeting multiple signaling pathways, reduce thelikelihood of drug-resistance arising in a cell, and reduce the toxicityof treatments for disease.

Kinases to which the present compounds bind and/or modulate (e.g.,inhibit) include any member of the PI3K family. In some embodiments, thePI3K is PI3Kα, PI3Kβ, PI3Kγ, or PI3Kδ. In some embodiments, the PI3K isPI3Kγ or PI3Kδ. In some embodiments, the PI3K is PI3Kγ. In someembodiments, the PI3K is PI3Kδ. In some embodiments, the PI3K includes amutation. A mutation can be a replacement of one amino acid for another,or a deletion of one or more amino acids. In such embodiments, themutation can be present in the kinase domain of the PI3K.

In some embodiments, more than one compound of the invention is used toinhibit the activity of one kinase (e.g., PI3Kγ or PI3Kδ).

In some embodiments, more than one compound of the invention is used toinhibit more than one kinase, such as at least two kinases (e.g., PI3Kγand PI3Kδ).

In some embodiments, one or more of the compounds is used in combinationwith another kinase inhibitor to inhibit the activity of one kinase(e.g., PI3Kγ or PI3Kδ).

In some embodiments, one or more of the compounds is used in combinationwith another kinase inhibitor to inhibit the activities of more than onekinase (e.g., PI3Kγ or PI3Kδ), such as at least two kinases.

The compounds of the invention can be selective. By “selective” is meantthat the compound binds to or inhibits a kinase with greater affinity orpotency, respectively, compared to at least one other kinase. In someembodiments, the compounds of the invention are selective inhibitors ofPI3Kγ or PI3Kδ over PI3Kα and/or PI3Kβ. In some embodiments, thecompounds of the invention are selective inhibitors of PI3Kδ (e.g., overPI3Kα, PI3Kβ and PI3Kγ). In some embodiments, the compounds of theinvention are selective inhibitors of PI3Kγ(e.g., over PI3Kα, PI3Kβ andPI3Kδ). In some embodiments, selectivity can be at least about 2-fold,5-fold, 10-fold, at least about 20-fold, at least about 50-fold, atleast about 100-fold, at least about 200-fold, at least about 500-foldor at least about 1000-fold. Selectivity can be measured by methodsroutine in the art. In some embodiments, selectivity can be tested atthe K_(m) ATP concentration of each enzyme. In some embodiments, theselectivity of compounds of the invention can be determined by cellularassays associated with particular PI3K kinase activity.

Another aspect of the present invention pertains to methods of treatinga kinase (such as PI3K)-associated disease or disorder in an individual(e.g., patient) by administering to the individual in need of suchtreatment a therapeutically effective amount or dose of one or morecompounds of the present invention or a pharmaceutical compositionthereof. A PI3K-associated disease can include any disease, disorder orcondition that is directly or indirectly linked to expression oractivity of the PI3K, including overexpression and/or abnormal activitylevels. In some embodiments, the disease can be linked to Akt (proteinkinase B), mammalian target of rapamycin (mTOR), orphosphoinositide-dependent kinase 1 (PDK1). In some embodiments, themTOR-related disease can be inflammation, atherosclerosis, psoriasis,restenosis, benign prostatic hypertrophy, bone disorders, pancreatitis,angiogenesis, diabetic retinopathy, atherosclerosis, arthritis,immunological disorders, kidney disease, or cancer. A PI3K-associateddisease can also include any disease, disorder or condition that can beprevented, ameliorated, or cured by modulating PI3K activity. In someembodiments, the disease is characterized by the abnormal activity ofPI3K. In some embodiments, the disease is characterized by mutant PI3K.In such embodiments, the mutation can be present in the kinase domain ofthe PI3K.

Examples of PI3K-associated diseases include immune-based diseasesinvolving the system including, for example, rheumatoid arthritis,allergy, asthma, glomerulonephritis, lupus, or inflammation related toany of the above.

Further examples of PI3K-associated diseases include cancers such asbreast, prostate, colon, endometrial, brain, bladder, skin, uterus,ovary, lung, pancreatic, renal, gastric, or hematological cancer.

In some embodiments, the hematological cancer is acute myeloblasticleukemia (AML) or chronic myeloid leukemia (CML), or B cell lymphoma.

Further examples of PI3K-associated diseases include lung diseases suchas acute lung injury (ALI) and adult respiratory distress syndrome(ARDS).

Further examples of PI3K-associated diseases include osteoarthritis,restenosis, atherosclerosis, bone disorders, arthritis, diabeticretinopathy, psoriasis, benign prostatic hypertrophy, inflammation,angiogenesis, pancreatitis, kidney disease, inflammatory bowel disease,myasthenia gravis, multiple sclerosis, or Sjögren's syndrome, and thelike.

Further examples of PI3K-associated diseases include idiopathicthrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA),vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus,membranous nephropathy, chronic lymphocytic leukemia (CLL), Non-Hodgkinlymphoma, hairy cell leukemia, Mantle cell lymphoma, Burkitt lymphoma,small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacyticlymphoma, extranodal marginal zone lymphoma, activated B-cell like (ABC)diffuse large B cell lymphoma, or germinal center B cell (GCB) diffuselarge B cell lymphoma.

In some embodiments, the ITP is relapsed ITP. In some embodiments, theITP is refractory ITP.

In some embodiments, the method is a method of treating autoimmunehemolytic anemia (AIHA).

In some embodiments, the method is a method of treating vasculitis. Insome embodiments, the vasculitis is Behcet's disease, Cogan's syndrome,giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu'sarteritis, Buerger's disease (thromboangiitis obliterans), centralnervous system vasculitis, Kawasaki disease, polyarteritis nodosa,Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis (essential orhepatitis C virus (HCV)-induced), Henoch-Schonlein purpura (HSP),hypersensitivity vasculitis, microscopic polyangiitis, Wegener'sgranulomatosis, or anti-neutrophil cytoplasm antibody associated (ANCA)systemic vasculitis (AASV). In some embodiments, the method is a methodof treating nephritis.

In some embodiments, the method of treating non-Hodgkin lymphoma (NHL)is relapsed or refractory NHL or recucurrent follicular NHL.

In some embodiments, the present application provides a method oftreating an aggressive lymphoma (e.g., germinal center B cell-like (GCB)or activated B cell-like (ABC)) in a patient, comprising administering atherapeutic amount of any of the compounds described herein to saidpatient, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides a method oftreating acute myloid leukemia in a patient, comprising administering atherapeutic amount of any of the compounds described herein to saidpatient, or a pharmaceutically acceptable salt thereof.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a PI3K with a compound of the invention includesthe administration of a compound of the present invention to anindividual or patient, such as a human, having a PI3K, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the PI3K.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician. In some embodiments, the dosage ofthe compound, or a pharmaceutically acceptable salt thereof,administered to a patient or individual is about 1 mg to about 2 g,about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg toabout 100 mg, about 1 mg to 50 mg, or about 50 mg to about 500 mg.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) preventing the disease; for example, preventing a disease,condition or disorder in an individual who may be predisposed to thedisease, condition or disorder but does not yet experience or displaythe pathology or symptomatology of the disease; (2) inhibiting thedisease; for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology); and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

Combination Therapies

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, EGFR, HER2, JAK (e.g.,JAK1 or JAK2), c-MET, VEGFR, PDGFR, cKit, IGF-1R, RAF, FAK, Akt mTOR,PIM, and AKT (e.g., AKT1, AKT2, or AKT3) kinase inhibitors such as, forexample, those described in WO 2006/056399, or other agents such as,therapeutic antibodies can be used in combination with the compounds ofthe present invention for treatment of PI3K-associated diseases,disorders or conditions. The one or more additional pharmaceuticalagents can be administered to a patient simultaneously or sequentially.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present invention and are presented as a non limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa,Tarceva, antibodies to EGFR, Gleevec™, intron, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17. alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine,cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine,Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP,MDL-101,731, bendamustine (Treanda), ofatumumab, and GS-1101 (also knownas CAL-101).

Example chemotherapeutics include proteosome inhibitors (e.g.,bortezomib), thalidomide, revlimid, and DNA-damaging agents such asmelphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include coriticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include the compounds, and pharmaceuticallyacceptable salts thereof, of the genera and species disclosed in U.S.Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 03/037347, WO03/099771, and WO 04/046120.

Example suitable RAF inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO05/028444.

Example suitable FAK inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 04/080980, WO04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402.

Example suitable mTOR inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 2011/025889.

In some embodiments, the compounds of the invention can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the invention can be used incombination with a chemotherapeutic in the treatment of cancer, such asmultiple myeloma, and may improve the treatment response as compared tothe response to the chemotherapeutic agent alone, without exacerbationof its toxic effects. Examples of additional pharmaceutical agents usedin the treatment of multiple myeloma, for example, can include, withoutlimitation, melphalan, melphalan plus prednisone [MP], doxorubicin,dexamethasone, and Velcade (bortezomib).

Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. Additive orsynergistic effects are desirable outcomes of combining a PI3K inhibitorof the present invention with an additional agent. Furthermore,resistance of multiple myeloma cells to agents such as dexamethasone maybe reversible upon treatment with the PI3K inhibitor of the presentinvention. The agents can be combined with the present compound in asingle or continuous dosage form, or the agents can be administeredsimultaneously or sequentially as separate dosage forms.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of theinvention where the dexamethasone is administered intermittently asopposed to continuously.

In some further embodiments, combinations of the compounds of theinvention with other therapeutic agents can be administered to a patientprior to, during, and/or after a bone marrow transplant or stem celltransplant.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the invention contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the invention.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating PI3K in tissue samples,including human, and for identifying PI3K ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes PI3Kassays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.For example, for in vitro PI3K labeling and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵, ¹³¹I, ³⁵S or willgenerally be most useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, one or more H atomsfor any compound described herein is each replaced by a deuterium atom.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a PI3K by monitoring its concentrationvariation when contacting with the PI3K, through tracking of thelabeling. For example, a test compound (labeled) can be evaluated forits ability to reduce binding of another compound which is known to bindto a PI3K (i.e., standard compound). Accordingly, the ability of a testcompound to compete with the standard compound for binding to the PI3Kdirectly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of PI3K-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to be PI3Kinhibitors according to at least one assay described herein.

EXAMPLES

The example compounds below containing one or more chiral centers wereobtained in racemate form or as isomeric mixtures, unless otherwisespecified. Salt stoichiometry which is indicated in any of the productsbelow is meant only to indicate a probable stoichiometry, and should notbe construed to exclude the possible formation of salts in otherstoichiometries.

Example 1. tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

Step 1. tert-Butyl[2-(6-acetyl-2-bromo-4-chloro-3-methylphenoxy)ethyl]carbamate

A suspension of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone(8.0 g, 30 mmol) in methylene chloride (304 mL) was heated with a heatgun to dissolve the solids and cooled to 0° C. To the mixture was addedtriphenylphosphine (11 g, 43 mmol) and tert-butyl(2-hydroxyethyl)carbamate (9.4 mL, 61 mmol). Diisopropylazodicarboxylate (8.4 mL, 43 mmol) was added dropwise. The mixture wasstirred for 23 hours at room temperature. The reaction mixture waspoured into water and extracted with methylene chloride. The organiclayer was separated, washed with brine, dried with sodium sulfate,filtered, and concentrated. The oil was dissolved in methylene chlorideand was purified on silica using ethyl acetate in hexanes (0-25%) togive the desired compound (7.3 g, 59%). LCMS calculated forC₁₆H₂₁BrClNO₄Na (M+Na)⁺: m/z=428.0, 430.0; found: 428.0, 430.0.

Step 2. tert-Butyl[2-(6-acetyl-4-chloro-3-methyl-2-vinylphenoxy)ethyl]carbamate

A mixture of tert-butyl[2-(6-acetyl-2-bromo-4-chloro-3-methylphenoxy)ethyl]carbamate (6.5 g, 16mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.3 mL, 19mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II),complex with dichloromethane (1:1) (600 mg, 0.8 mmol) and potassiumcarbonate (6.6 g, 48 mmol) in 1,4-dioxane (100 mL), and water (50 mL)was heated at 80° C. for 3 hours and 50° C. overnight. The reactionmixture was cooled to room temperature and extracted with ethyl acetate(3×10 mL). The organic layers were combined and washed with brine, driedover magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified on a silica gel with ethyl acetate inhexanes (0-25%) to afford the desired compound (4.1 g, 72%). LCMScalculated for C₁₈H₂₄ClNO₄Na (M+Na)⁺: m/z=376.1. found: 376.0.

Step 3. tert-Butyl[2-(6-acetyl-4-chloro-2-formyl-3-methylphenoxy)ethyl]carbamate

tert-Butyl [2-(6-acetyl-4-chloro-3-methyl-2-vinylphenoxy)ethyl]carbamate(4.1 g, 12 mmol) was dissolved in tetrahydrofuran (300 mL) and 0.157 Mosmium tetraoxide in water (10 mL) was added followed by a solution ofsodium metaperiodate (7.4 g, 35 mmol) in water (20 mL). The reaction wasstirred at 60° C. for 2 hours. Additional 0.157 M osmium tetraoxide inwater (10 mL) and a solution of sodium metaperiodate (7.4 g, 35 mmol) inwater (20 mL) were added and the mixture was heated at 60° C. for 2 morehours. The mixture was poured into ethyl acetate and washed with water,brine, dried over sodium sulfate, filtered and evaporated. Purificationon silica gel using ethyl acetate in hexanes (0-12%) gave the desiredcompound (3.0 g, 73%) (note: elutes as 2 separate peaks in both normaland reversed phase chromatography). LCMS calculated for C₁₇H₂₂ClNO₅Na(M+Na)⁺: m/z=378.1; found: 378.0.

Step 4. 1-(7-Chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-9-yl)ethanone

tert-Butyl[2-(6-acetyl-4-chloro-2-formyl-3-methylphenoxy)ethyl]carbamate (270 mg,0.76 mmol) was stirred in 4.0 M hydrogen chloride in dioxane (5.0 mL) atroom temperature for 1 hour and evaporated. Tetrahydrofuran was addedand the mixture was evaporated to give the desired compound (180 mg,100%). LCMS calculated for C₁₂H₁₃ClNO₂ (M+H)⁺: m/z=238.1. found: 238.0.

Step 5.1-(7-Chloro-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethanol

1-(7-Chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-9-yl)ethanone (630 mg,2.6 mmol) was stirred in methanol (20 mL) and cooled to 0° C. Sodiumtetrahydroborate (150 mg, 4.0 mmol) was added. The mixture was stirredfor 1 hour at room temperature and evaporated. The mixture was extractedwith ethyl acetate, washed with saturated sodium bicarbonate, brine,dried over sodium sulfate, filtered and evaporated gave the desiredcompound (580 mg, 90%). LCMS calculated for C₁₂H₁₇ClNO₂ (M+H)⁺:m/z=242.1; found: 242.0.

Step 6. tert-Butyl7-chloro-9-(1-hydroxyethyl)-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

1-(7-Chloro-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethanol(250 mg, 1.0 mmol) and di-tert-butyldicarbonate (220 mg, 1.0 mmol) werestirred in tetrahydrofuran (12 mL) and N,N-diisopropylethylamine (1.3mL, 7.2 mmol) was added. The mixture was stirred at room temperature for1 hour. The mixture was diluted with saturated bicarbonate and extractedwith ethyl acetate. The extracts were washed with brine, dried oversodium sulfate, filtered and evaporated to give the crude. Purificationon silica gel using ethyl acetate in hexanes 0-35% gave the desiredcompound (89%). LCMS calculated for C₁₇H₂₄ClNO₄Na (M+Na)⁺: m/z=364.1;found: 364.0.

Step 7. tert-Butyl7-chloro-9-(1-chloroethyl)-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

A mixture of tert-butyl7-chloro-9-(1-hydroxyethyl)-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(280 mg, 0.82 mmol) and N,N-dimethylformamide (30 μL) in methylenechloride (6 mL) was stirred and thionyl chloride (120 μL, 1.7 mmol) wasadded dropwise. The mixture was stirred at room temperature for 20minutes. The mixture was diluted with methylene chloride, washed withsaturated sodium bicarbonate, water, brine, dried over sodium sulfate,filtered and concentrated to give the desired product (295 mg, 100%).

Step 8. tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

Cesium carbonate (500 mg, 2 mmol) was added to a mixture of3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.98 mmol) inN,N-dimethylformamide (30 mL) and stirred for 10 minutes. To this wasadded tert-butyl7-chloro-9-(1-chloroethyl)-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(290 mg, 0.82 mmol) in N,N-dimethylformamide (1 mL) and the reaction wasstirred at 80° C. for 1 hour. The mixture was diluted with ethyl acetateand washed with water and brine. The extracts were dried over sodiumsulfate, filtered and evaporated. The crude was dissolved in methylenechloride and filtered to remove insoluble material (unwantedregioisomer). Purification on silica gel using ethyl acetate in hexanes(0-100%) followed by methanol in ethyl acetate (0-15%) gave the desiredcompound (240 mg, 62%). LCMS calculated for C₂₃H₃₀ClN₆O₃ (M+H)⁺:m/z=473.2; found: 473.2. ¹H NMR (300 MHz, CD₃OD): δ 8.14 (s, 1H), 7.29(m, 1H), 6.32 (m, 1H), 4.70 (m, 1H), 4.40 (m, 1H), 3.83 (m, 2H), 3.57(m, 2H), 2.58 (s, 3H), 2.48 (m, 3H), 1.78 (m, 3H), 1.39 (m, 9H).

Example 2.1-[1-(7-Chloro-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(10 mg, 0.02 mmol) was stirred in 4 N HCl in dioxane (1 mL), and thenthe solvent was evaporated. Purification by preparative LCMS (pH 2) gavethe desired compound (1.8 mg, 7%). LCMS calculated for C₁₈H₂₂ClN₆O(M+H)⁺: m/z=373.2; found: 373.1.

Example 3. tert-Butyl3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate

tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(100 mg, 0.2 mmol) was treated with 4 N HCl in dioxane (1 mL), and thenthe solvent was evaporated. The residue was stirred in methanol (5 mL)and tert-butyl 3-oxoazetidine-1-carboxylate (140 mg, 0.84 mmol) wasadded. Sodium cyanoborohydride (120 mg, 1.9 mmol) was added and themixture was warmed to 60° C. for 1.5 hours. Purification by preparativeLCMS (pH 10) gave the desired compound (3.3 mg, 10%). LCMS calculatedfor C₂₆H₃₅ClN₇O₃ (M+H)⁺: m/z=528.2; found: 528.3. ¹H NMR (300 MHz,CD₃OD): δ 8.14 (s, 1H), 7.33 (s, 1H), 6.33 (m, 1H), 4.00 (m, 2H), 3.82(m, 1H), 3.74 (m, 2H), 3.63 (m, 3H), 3.41 (m, 1H), 2.76 (m, 2H), 2.58(s, 3H), 2.37 (s, 3H), 1.79 (m, 3H), 1.42 (s, 9H).

Example 4.1-{1-[4-(1-Acetylazetidin-3-yl)-7-chloro-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

tert-Butyl3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate(15 mg, 0.035 mmol) was treated with 4 N HCl in dioxane (1 mL), and thenthe solvent was evaporated. The residue was stirred inN,N-dimethylformamide (0.5 mL) with N,N-diisopropylethylamine (10 μL,0.06 mmol) and acetic anhydride (20 μL, 0.2 mmol) was added. The mixturewas stirred for 5 minutes and diluted with methanol. Purification bypreparative LCMS (pH 10) gave the desired compound (2.2 mg, 13%). LCMScalculated for C₂₃H₂₉ClN₇O₂ (M+H)⁺: m/z=470.2; found: 470.2. ¹H NMR (300MHz, CD₃OD): δ 8.14 (s, 1H), 7.33 (s, 1H), 6.33 (m, 1H), 4.27 (m, 1H),4.02 (m, 2H), 3.80 (m, 1H), 3.72 (m, 1H), 3.69 (m, 3H), 3.48 (m, 1H),2.79 (m, 2H), 2.58 (s, 3H), 2.38 (s, 3H), 1.82 (m, 3H), 1.77 (m, 3H).

Example 5.1-[1-(7-Chloro-4-cyclobutyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

The desired compound was prepared according to the procedure of Example3, using cyclobutanone instead of tert-butyl3-oxoazetidine-1-carboxylate as the starting material in 50% yield. LCMScalculated for C₂₂H₂₈ClN₆O (M+H)⁺: m/z=427.2; found: 427.0. ¹H NMR (300MHz, CD₃OD): δ 8.31 (s, 1H), 7.61 (s, 1H), 6.47 (m, 1H), 4.37 (s, 2H),3.89 (m, 1H), 3.48 (m, 2H), 2.64 (s, 3H), 2.45 (m, 4H), 2.28 (m, 1H),1.86 (m, 3H).

Example 6.1-[1-(7-Chloro-4-cyclopentyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

The desired compound was prepared according to the procedure of Example3, using cyclopentanone instead of tert-butyl3-oxoazetidine-1-carboxylate as the starting material in 50% yield. LCMScalculated for C₂₃H₃₀ClN₆O (M+H)⁺: m/z=441.2; found: 441.0. ¹H NMR (300MHz, CD₃OD): δ 8.31 (s, 1H), 7.60 (s, 1H), 6.47 (m, 1H), 4.52 (br s,2H), 3.79 (m, 1H), 3.62 (m, 2H), 2.63 (s, 3H), 2.47 (s, 3H), 2.03 (m,3H), 1.81 (m, 10H).

Example 7.1-[1-(7-Chloro-4-cyclohexyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

The desired compound was prepared according to the procedure of Example3, using cyclohexanone instead of tert-butyl3-oxoazetidine-1-carboxylate as the starting material in 20% yield. LCMScalculated for C₂₄H₃₂ClN₆O (M+H)⁺: m/z=455.2; found: 455.2. ¹H NMR (300MHz, CD₃OD): δ 8.30 (s, 1H), 7.59 (s, 1H), 6.48 (m, 1H), 4.60 (m, 2H),4.48 (m, 2H), 3.75 (m, 1H), 3.47 (m, 2H), 2.63 (s, 3H), 2.48 (s, 3H),2.18 (m, 2H), 2.03 (m, 2H), 1.85 (m, 3H), 1.73 (m, 3H), 1.47 (m, 2H),1.29 (m, 1H).

Example 8.1-{1-[7-Chloro-4-(4-methoxycyclohexyl)-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

The desired compound was prepared according to the procedure of Example3, using 4-methoxycyclohexanone instead of tert-butyl3-oxoazetidine-1-carboxylate as the starting material in 10% yield. LCMScalculated for C₂₅H₃₄ClN₆O₂ (M+H)⁺: m/z=485.2; found: 485.3. ¹H NMR (300MHz, CD₃OD): δ 8.51 (s, 1H), 7.56 (s, 1H), 6.48 (m, 1H), 4.60 (m, 2H),4.48 (m, 2H), 3.75 (m, 1H), 3.47 (m, 2H), 3.30 (m, 4H), 2.62 (s, 3H),2.48 (s, 3H), 2.20 (m, 2H), 1.85 (m, 6H), 1.60 (m, 2H), 1.29 (m, 1H).

Example 9.1-[1-(7-Chloro-4,6-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(10 mg, 0.02 mmol) (treated with 4 N HCl in dioxane, and then thesolvent was evaporated) was stirred in 3.0 M formaldehyde in water (0.5mL, 2 mmol) and formic acid (0.5 mL, 10 mmol) was added. The mixture washeated to 90° C. for 10 minutes. Purification by preparative LCMS (pH 2)gave the desired compound (3.0 mg, 20%). LCMS calculated for C₁₉H₂₄ClN₆O(M+H)⁺: m/z=387.2; found: 387.1. ¹H NMR (300 MHz, CD₃OD): δ 8.30 (s,1H), 7.60 (s, 1H), 6.47 (m, 1H), 4.55 (m, 2H), 4.25 (m, 1H), 3.60 (m,3H), 3.03 (s, 3H), 2.64 (s, 3H), 2.47 (s, 3H), 1.85 (m, 3H).

Example 10.1-[1-(7-Chloro-4-isopropyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(15 mg, 0.032 mmol) (treated with 4 N HCl in dioxane, and then thesolvent was evaporated) was stirred in acetone (1.0 mL, 14 mmol) andsodium cyanoborohydride (6.0 mg, 0.095 mmol) was added. The mixture wasstirred overnight. Purification by preparative LCMS (pH 2) gave thedesired compound (7.0 mg, 34%). LCMS calculated for C₂₁H₂₈ClN₆O (M+H)⁺:m/z=415.2; found: 415.1. ¹H NMR (300 MHz, CD₃OD): δ 8.31 (s, 1H), 7.59(s, 1H), 6.47 (br s, 1H), 4.49 (m, 4H), 3.80 (m, 2H), 3.50 (m, 1H), 2.64(s, 3H), 2.48 (s, 3H), 1.86 (m, 3H), 1.46 (m, 6H).

Example 11.[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]acetonitrilebis(trifluoroacetate)

tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(10 mg, 0.02 mmol) (treated with 4 N HCl in dioxane, and then thesolvent was evaporated) was stirred in N-methylpyrrolidinone (1.0 mL)and N,N-diisopropylethylamine (0.0082 g, 0.063 mmol) was added.Bromoacetonitrile (5.1 mg, 0.042 mmol) was added and the mixture waswarmed to 80° C. for 1 hour. Purification by preparative LCMS (pH 2)gave the desired compound (4.9 mg, 40%). LCMS calculated for C₂₀H₂₃ClN₇O(M+H)⁺: m/z=412.2; found: 412.1. ¹H NMR (300 MHz, CD₃OD): δ 8.30 (s,1H), 7.38 (s, 1H), 6.46 (m, 1H), 4.03 (m, 1H), 3.91 (s, 2H), 3.81 (m,3H), 3.05 (m, 2H), 2.65 (s, 3H), 2.41 (s, 3H), 1.83 (m, 3H).

Example 12.3-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-3-oxopropanenitriletrifluoroacetate

tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(10 mg, 0.02 mmol) (treated with 4 N HCl in dioxane, and then thesolvent was evaporated) was stirred in N-methylpyrrolidinone (1.0 mL)and N,N-diisopropylethylamine (0.0082 g, 0.063 mmol) was added.3-[(2,5-Dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (0.008 g, 0.042mmol) was added and the mixture was warmed to 80° C. for 1 hour.Purification by preparative LCMS (pH 2) gave the desired compound (1.8mg, 20%). LCMS calculated for C₂₁H₂₃ClN₇O₂ (M+H)⁺: m/z=440.2; found:440.3. ¹H NMR (300 MHz, CD₃OD): δ 8.28 (s, 1H), 7.38 (s, 1H), 6.45 (m,1H), 4.88 (m, 1H), 4.54 (m, 1H), 3.82 (m, 5H), 2.65 (s, 3H), 2.56 (s,3H), 1.83 (m, 3H).

Example 13.1-{1-[7-Chloro-6-methyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(10 mg, 0.02 mmol) (treated with 4 N HCl in dioxane, and then thesolvent was evaporated) was stirred in tetrahydrofuran (0.5 mL) withN,N-diisopropylethylamine (18 μL, 0.10 mmol) and methanesulfonylchloride (1.6 μL, 0.021 mmol) was added. The mixture was stirred at roomtemperature for 20 minutes. Purification by preparative LCMS (pH 2) gavethe desired compound (6.3 mg, 53%). LCMS calculated for C₁₉H₂₄ClN₆O₃S(M+H)⁺: m/z=451.1; found: 451.0. ¹H NMR (300 MHz, CD₃OD): δ 8.29 (s,1H), 7.41 (s, 1H), 6.47 (m, 1H), 4.62 (m, 1H), 4.43 (m, 1H), 4.12 (m,1H), 3.74 (m, 3H), 2.81 (s, 3H), 2.65 (s, 3H), 2.44 (s, 3H), 1.83 (m,3H).

Example 14.1-{1-[7-Chloro-6-methyl-4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

The desired compound was prepared according to the procedure of Example13, using bezenesulfonyl chloride instead of methanesulfonyl chloride in53% yield. LCMS calculated for C₂₄H₂₆ClN₆O₃S (M+H)⁺: m/z=513.1; found:513.0. ¹H NMR (300 MHz, CD₃OD): δ 8.26 (s, 1H), 7.70 (m, 2H), 7.49 (m,4H), 6.36 (m, 1H), 4.60 (m, 1H), 4.33 (m, 1H), 3.97 (m, 1H), 3.62 (m,3H), 2.65 (s, 3H), 2.51 (s, 3H), 1.77 (m, 3H).

Example 15.9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-N-(2-methylphenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxamidetrifluoroacetate

The desired compound was prepared according to the procedure of Example13, using 1-isocyanato-2-methylbenzene instead of methanesulfonylchloride in 27% yield. LCMS calculated for C₂₆H₂₉ClN₇O₂ (M+H)⁺:m/z=506.2; found: 506.0. ¹H NMR (300 MHz, CD₃OD): δ 8.29 (s, 1H), 7.36(s, 1H), 7.08 (m, 4H), 6.49 (m, 1H), 4.80 (m, 1H), 4.60 (m, 1H), 4.12(m, 1H), 3.88 (m, 3H), 2.65 (s, 3H), 2.47 (s, 3H), 1.95 (s, 3H), 1.84(m, 3H).

Example 16.1-[1-(4-Benzoyl-7-chloro-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

The desired compound was prepared according to the procedure of Example13, using benzoyl chloride instead of methanesulfonyl chloride,Purification by preparative LCMS (pH 2) gave the desired compound (2.1mg, 17%). LCMS calculated for C₂₅H₂₆ClN₆O₂ (M+H)⁺: m/z=477.2; found:477.0. ¹H NMR (300 MHz, CD₃OD): δ 8.27 (s, 1H), 7.42 (s, 6H), 6.46 (m,1H), 4.89 (m, 1H), 4.79 (m, 1H), 4.00 (m, 1H), 3.77 (m, 3H), 2.64 (m,6H), 1.83 (m, 3H).

Example 17.1-(1-{7-Chloro-4-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl}yl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(10 mg, 0.02 mmol) (treated with 4 N HCl in dioxane, and then thesolvent was evaporated) was stirred in methylene chloride (1.0 mL) withN,N-diisopropylethylamine (11 μL, 0.063 mmol) and3,5-dimethylisoxazole-4-sulfonyl chloride (8.3 mg, 0.042 mmol) wasadded. The mixture was stirred at room temperature for 20 minutes.Purification by preparative LCMS (pH 2) gave the desired compound (3.1mg, 20%). LCMS calculated for C₂₃H₂₇ClN₇O₄S (M+H)⁺: m/z=532.1; found:532.2. ¹H NMR (300 MHz, CD₃OD): δ 8.29 (s, 1H), 7.42 (s, 1H), 6.38 (m,1H), 4.70 (m, 1H), 4.52 (m, 1H), 4.12 (m, 1H), 3.83 (m, 1H), 3.66 (m,2H), 2.65 (s, 3H), 2.50 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H), 1.80 (m,3H).

Example 18.1-{1-[7-Chloro-4-(cyclopropylsulfonyl)-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

The desired compound was prepared according to the procedure of Example17, using cyclopropanesulfonyl chloride instead of methanesulfonylchloride in 20% yield. LCMS calculated for C₂₁H₂₆ClN₆O₃S (M+H)⁺:m/z=477.1; found: 477.1. ¹H NMR (300 MHz, CD₃OD): δ 8.29 (s, 1H), 7.40(s, 1H), 6.46 (m, 1H), 4.68 (m, 1H), 4.49 (m, 1H), 4.10 (m, 1H), 3.80(m, 1H), 3.71 (m, 2H), 2.64 (s, 3H), 2.45 (s, 3H), 2.28 (m, 1H), 1.83(m, 3H), 0.93 (m, 4H).

Example 19.1-[1-(4-Acetyl-7-chloro-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

The desired compound was prepared according to the procedure of Example1, steps 5-8 using acetic anhydride instead of di-tert-butyldicarbonatein 10% yield. LCMS calculated for C₂₀H₂₄ClN₆O₂ (M+H)⁺: m/z=415.2; found:415.0. ¹H NMR (300 MHz, CDCl₃): δ 8.19 (s, 1H), 7.43 (s, 1H), 6.44 (m,1H), 4.78 (m, 1H), 4.58 (m, 1H), 4.04 (m, 1H), 3.86 (m, 3H), 2.67 (s,3H), 2.58 (s, 3H), 2.10 (s, 3H), 1.84 (m, 3H).

Example 20.1-[1-(7-Chloro-6-methyl-4-propionyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

The desired compound was prepared according to the procedure of Example1, steps 5-8 using propanoyl chloride instead ofdi-tert-butyldicarbonate in 10% yield. LCMS calculated for C₂₁H₂₆ClN₆O₂(M+H)⁺: m/z=429.2; found: 429.0. ¹H NMR (300 MHz, CD₃OD): δ 8.28 (s,1H), 7.35 (s, 1H), 6.49 (m, 1H), 4.78 (m, 1H), 4.59 (m, 1H), 4.10 (m,1H), 3.80 (m, 3H), 2.64 (s, 3H), 2.56 (s, 3H), 2.28 (m, 2H), 1.82 (m,3H), 1.03 (m, 3H).

Example 21.1-{1-[7-Chloro-4-(methoxyacetyl)-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

The desired compound was prepared according to the procedure of Example1, steps 5-8 using methoxyacetyl chloride instead ofdi-tert-butyldicarbonate in 10% yield. LCMS calculated for C₂₁H₂₆ClN₆O₃(M+H)⁺: m/z=445.2; found: 445.0. ¹H NMR (300 MHz, CD₃OD): δ 8.30 (s,1H), 7.34 (s, 1H), 6.49 (m, 1H), 4.78 (m, 1H), 4.59 (m, 1H), 4.10 (m,4H), 3.77 (m, 3H), 3.30 (m, 2H), 2.65 (s, 3H), 2.57 (s, 3H), 1.82 (m,3H).

Example 22.1-[1-(7-Chloro-4-isobutyryl-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminetrifluoroacetate

The desired compound was prepared according to the procedure of Example1, steps 5-8 using isobutyryl chloride instead ofdi-tert-butyldicarbonate, 23%. LCMS calculated for C₂₂H₂₈ClN₆O₂ (M+H)⁺:m/z=443.2; found: 443.0. ¹H NMR (300 MHz, CD₃OD): δ 8.28 (s, 1H), 7.34(s, 1H), 6.45 (m, 1H), 4.75 (m, 1H), 4.55 (m, 1H), 4.10 (m, 1H), 3.80(m, 3H), 2.80 (m, 1H), 2.63 (s, 3H), 2.56 (s, 3H), 1.82 (m, 3H), 1.00(m, 6H).

Example 23.2-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-1,3-thiazole-5-carbonitriletrifluoroacetate

tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(10 mg, 0.02 mmol) (treated with 4 N HCl in dioxane, and then thesolvent was evaporated) was stirred in NMP and2-chloro-1,3-thiazole-5-carbonitrile (10 mg, 0.07 mmol) was added. Themixture was heated to 130° C. for 1 hour. Purification by preparativeLCMS (pH 10) gave the desired compound (3.2 mg, 30%). LCMS calculatedfor C₂₂H₂₂ClN₈OS (M+H)⁺: m/z=481.1; found: 481.1. ¹H NMR (300 MHz,CD₃OD): δ 8.14 (s, 1H), 7.74 (s, 1H), 7.31 (s, 1H), 6.31 (m, 1H), 4.99(m, 1H), 4.78 (m, 1H), 3.98 (m, 3H), 3.75 (m, 1H), 2.58 (m, 6H), 1.77(m, 3H).

Example 24.1-[1-(7-Chloro-6-methyl-4-pyrazin-2-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-aminebis(trifluoroacetate)

The desired compound was prepared according to the procedure of Example23, using 2-chloropyrazine instead of2-chloro-1,3-thiazole-5-carbonitrile in 10% yield. LCMS calculated forC₂₂H₂₄ClN₈O (M+H)⁺: m/z=451.2; found: 451.1. ¹H NMR (300 MHz, DMSO-d₆):δ 8.28 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.24 (s, 1H),6.31 (m, 1H), 4.89 (m, 1H), 4.75 (m, 1H), 4.05 (m, 3H), 3.75 (m, 1H),2.58 (m, 6H), 1.68 (m, 3H).

Example 25.9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-onetrifluoroacetate

Step 1.3-Acetyl-2-{2-[(tert-butoxycarbonyl)amino]ethoxy}-5-chloro-6-methylbenzoicacid

tert-Butyl[2-(6-acetyl-4-chloro-2-formyl-3-methylphenoxy)ethyl]carbamate (85 mg,0.24 mmol) was stirred in methanol (7 mL) and 1.0 M sodium hydroxide inwater (2.7 mL) and urea hydrogen peroxide addition compound (200 mg, 2mmol) was added. Additional urea hydrogen peroxide addition compound (20mg) and 1.0 M sodium hydroxide in water (0.5 mL) were added and themixture was stirred for 3 more hours. 1 N HCl was added to pH 5 and themethanol was evaporated. The mixture was extracted with ethyl acetate,washed with brine, dried over sodium sulfate, filtered and evaporated togive the desired compound (75 mg, 84%). LCMS calculated forC₁₇H₂₂ClNO₆Na (M+Na)⁺: m/z=394.1; found: 393.9.

Step 2.2-{2-[(tert-Butoxycarbonyl)amino]ethoxy}-5-chloro-3-(1-hydroxyethyl)-6-methylbenzoicacid

Sodium tetrahydroborate (6.1 mg, 0.16 mmol) was added to a mixture of3-acetyl-2-{2-[(tert-butoxycarbonyl)amino]ethoxy}-5-chloro-6-methylbenzoicacid (40 mg, 0.1 mmol) in methanol (0.50 mL) at 0° C. and the reactionwas stirred at room temperature for 1 hour. The solvent was removed andthe residue was diluted with ethyl acetate, washed with saturated sodiumbicarbonate, adjusted the pH to 5 with 1 N hydrogen chloride solution,washed with brine, dried over sodium sulfate, filtered and concentratedto give the desired compound (30 mg, 70%). LCMS calculated forC₁₇H₂₄ClNO₆Na (M+Na)⁺: m/z=396.1; found: 396.0.

Step 3.7-Chloro-9-(1-hydroxyethyl)-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one

2-{2-[(tert-Butoxycarbonyl)amino]ethoxy}-5-chloro-3-(1-hydroxyethyl)-6-methylbenzoicacid (27 mg, 0.072 mmol) was stirred in 4.0 M hydrogen chloride in1,4-dioxane (3 mL) and evaporated. 1-Hydroxybenzotriazole hydrate (13mg, 0.087 mmol), N,N-diisopropylethylamine (63 μL, 0.36 mmol) andN,N-dimethylformamide (2.0 mL) were added and the mixture was stirredfor ten minutes. Benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate (38 mg, 0.087 mmol) was added and the mixture wasstirred at 30° C. overnight. The mixture was diluted with ethyl acetate,washed with brine, dried over sodium sulfate, filtered and evaporated togive the desired product (14 mg, 76%). LCMS calculated for C₁₂H₁₅ClNO₃(M+H)⁺: m/z=256.1; found: 256.0.

Step 4.7-Chloro-9-(1-chloroethyl)-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one

A mixture of cyanuric chloride (15 mg, 0.079 mmol),7-chloro-9-(1-hydroxyethyl)-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one(14 mg, 0.053 mmol) and N,N-dimethylformamide (20 μL) in methylenechloride (0.4 mL) was stirred at room temperature overnight. The mixturewas diluted with methylene chloride, washed with saturated sodiumbicarbonate, water, brine, dried over sodium sulfate, filtered andconcentrated to give the desired compound (10 mg, 70%).

Step 5.9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-onetrifluoroacetate

A mix of7-chloro-9-(1-chloroethyl)-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one(10 mg, 0.04 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6.5mg, 0.044 mmol), cesium carbonate (18 mg, 0.055 mmol) and potassiumiodide (0.60 mg, 0.0036 mmol) in N,N-dimethylformamide (0.12 mL) washeated at 140° C. for 1 hour. The mix was diluted with ethyl acetate,washed with water, concentrated and purified by preparative LCMS (pH 2)to give the desired compound (2.7 mg, 10%). LCMS calculated forC₁₈H₂₀ClN₆O₂ (M+H)⁺: m/z=387.1. found: 387.0. ¹H NMR (300 MHz, CD₃OD): δ8.26 (s, 1H), 7.61 (s, 1H), 6.48 (m, 1H), 4.25 (m, 4H), 2.65 (s, 3H),2.37 (s, 3H), 1.85 (m, 3H).

Examples 26 and 27. tert-Butyl3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate

Step 1. 1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone

To 4-chloro-3-fluorophenol (from Aldrich, 20 g, 100 mmol) was addedacetyl chloride (14.1 mL, 199 mmol) under N₂ with stirring. Theresulting mixture turned into a clear solution at room temperaturequickly and it was heated at 60° C. for 2 hours. To the resultantmixture was added aluminum trichloride (25.0 g, 187 mmol) in portionsand the reaction mixture was heated at 180° C. for 30 minutes. Thesolids slowly dissolved at high temperature. The reaction mixture wasthen cooled to room temperature while the flask was swirled carefully inorder for the solid to form a thin layer inside the flask and thenslowly quenched with 1.0 N HCl (300 mL) while cooling in an ice-bath andstirred overnight. The yellow precipitate was washed with water anddried under vacuum to give the desired product as a yellow solid (23.8g), which was directly used in the next step without furtherpurification.

Step 2. 1-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone

A solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (23.8 g, 126mmol) in acetic acid (100 mL) was treated with N-iodosuccinimide (34.1g, 151 mmol) and stirred at 70° C. for 2 hr. The reaction mixture wasconcentrated, diluted with EtOAc and quenched with sat. NaHCO₃ solutionuntil the bubbling stopped. The organic layers were separated, washedwith water, dried over MgSO₄ and stripped to give the desired productwhich was used in the next step without further purification.

Step 3. tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

The title compound was prepared by methods analogous to Example 1, steps1-8, but using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone andtert-butyl [(2R)-2-hydroxypropyl]carbamate (Alfa Aesar #H27296) inStep 1. Purification by preparative LCMS (pH 10) gave the desiredcompound (75 mg, 38%). LCMS calculated for C₂₃H₂₉ClFN₆O₃ (M+H)⁺:m/z=491.2; found: 491.2.

Step 4. tert-Butyl3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate

tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(75 mg, 0.15 mmol) was stirred in 4 NHCl in dioxane (5 mL) andevaporated. The residue was stirred in methanol (4 mL) and tert-butyl3-oxoazetidine-1-carboxylate (110 mg, 0.61 mmol) was added. Sodiumcyanoborohydride (86 mg, 1.4 mmol) was added and the mixture was warmedto 60° C. overnight and evaporated. Water was added and the mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The reactions werepurified by prep HPLC on C-18 column eluting water:acetonitrile gradientbuffered pH 10 to give two diastereomers (peak #1 and 2): Peak #1(Example 26): LCMS calculated for C₂₆H₃₄ClFN₇O₃ (M+H)⁺: m/z=546.2;found: 546.2 ¹H NMR (300 MHz, CD₃OD): δ 8.14 (s, 1H), 7.38 (m, 1H), 6.32(m, 1H), 4.11 (m, 1H), 3.95 (m, 2H), 3.78 (m, 2H), 3.50 (m, 2H), 2.92(m, 2H), 2.65 (m, 1H), 2.60 (s, 3H), 1.80 (m, 3H), 1.42 (s, 9H), 1.38(m, 3H). Peak #2 (Example 27): LCMS calculated for C₂₆H₃₄ClFN₇O₃ (M+H)⁺:m/z=546.2; Found: 546.2.

Examples 28 and 29.1-{1-[4-(1-Acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

tert-Butyl3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate(6 mg, 0.01 mmol) (Example 26, step 4, peak 1) was stirred in 4 NHCl indioxane for 30 minutes and evaporated to give the hydrochloride salt.The salt was stirred in N,N-dimethylformamide (0.2 mL) withN,N-diisopropylethylamine (6 μL, 0.03 mmol) and acetic anhydride (6 μL,0.07 mmol) was added. The mixture was stirred for 5 minutes and dilutedwith methanol (5 mL). Purification by preparative LCMS (pH 10) gave thedesired compound 3.3 mg (Example 28): LCMS calculated for C₂₃H₂₈ClFN₇O₂(M+H)⁺: m/z=488.2; found: 488.2 ¹H NMR (300 MHz, CD₃OD): δ 8.14 (s, 1H),7.38 (m, 1H), 6.32 (m, 1H), 4.20 (m, 2H), 4.00 (m, 2H), 3.80 (m, 1H),3.50 (m, 2H), 2.98 (m, 2H), 2.67 (m, 1H), 2.59 (s, 3H), 1.85 (s, 3H),1.80 (m, 3H), 1.39 (m, 3H).

Utilizing the same procedure starting with the material of Example 27(step 4, peak 2) produced 1.3 mg of product (Example 29): LCMScalculated for C₂₃H₂₈ClFN₇O₂ (M+H)⁺: m/z=488.2; found: 488.2 ¹H NMR (300MHz, CD₃OD): δ 8.14 (s, 1H), 7.38 (m, 1H), 6.32 (m, 1H), 4.20 (m, 1H),4.00 (m, 3H), 3.79 (m, 1H), 3.60 (m, 1H), 3.48 (m, 1H), 2.95 (m, 2H),2.71 (m, 1H), 2.60 (s, 3H), 1.85 (s, 3H), 1.77 (m, 3H), 1.31 (m, 3H).

Examples 30, 31, 32, and 33.1-{1-[4-(1-Acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

The diasteromers from Example 28 were separated into the respective twoenantiomers by chiral prep HPLC using a ChiralPAK IA column 5 μm, 20×250mm eluting 30% ethanol in hexanes at 18 mL/min, with 20 mg/mL loading togive two peaks: Peak #1 (Example 30), retention time 7.76 min.: LCMScalculated for C₂₃H₂₈ClFN₇O₂ (M+H)⁺: m/z=488.2; found: 488.2; Peak #2(Example 31), retention time 10.23 min: LCMS calculated forC₂₃H₂₈ClFN₇O₂ (M+H)⁺: m/z=488.2; found: 488.2.

The diasteromers from Example 29 were separated into the respective twoenantiomers by chiral prep HPLC using a ChiralPAK AD column 5 μm, 20×250mm eluting 20% ethanol in hexanes at 16 mL/min, with 20 mg/mL loading togive two peaks: Peak #1 (Example 32), retention time 7.63 min.: LCMScalculated for C₂₃H₂₈ClFN₇O₂ (M+H)⁺: m/z=488.2; found: 488.2; Peak #2(Example 33), retention time 11.36 min.: LCMS calculated forC₂₃H₂₈ClFN₇O₂ (M+H)⁺: m/z=488.2; found: 488.2.

Example 34.1-{1-[4-(1-Acetylazetidin-3-yl)-7-chloro-6-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1. tert-Butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

The title compound was prepared by methods analogous to Example 1, steps1-8, but using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone(from Examples 26-27, step 2) in step 1.

Step 2. tert-Butyl3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate

The title compound was prepared by methods analogous to Example 26, step2, but using tert-butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate.

Step 3.1-{1-[4-(1-acetylazetidin-3-yl)-7-chloro-6-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

tert-Butyl3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate(14 mg, 0.026 mmol) was stirred in 4 N HCl in dioxane for 30 minutes andevaporated to give the hydrochloride salt. The salt was stirred inN,N-dimethylformamide (0.4 mL) with N,N-diisopropylethylamine (10 μL,0.08 mmol) and acetic anhydride (10 μL, 0.2 mmol) was added. The mixturewas stirred for 5 minutes and diluted with methanol. Purification bypreparative LCMS (pH 10) gave the desired compound (Example 34). LCMScalculated for C₂₂H₂₆ClN₇O₂ (M+H)⁺: m/z=474.2. found: 474.2.

Examples 35 and 36.1-{1-[(3S)-7-Chloro-6-fluoro-3-methyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1. tert-Butyl(3S)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-3-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

The title compound was prepared by methods analogous to Example 1, steps1-8, but using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone(from Examples 26-27, step 2) and tert-butyl[(1S)-2-hydroxy-1-methylethyl]carbamate [Ald. #469513] in Step 1. LCMScalculated for C₂₃H₂₉ClFN₆O₃ (M+H)⁺: m/z=491.2; found: 491.2.

Step 2.1-{1-[(3S)-7-chloro-6-fluoro-3-methyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

tert-Butyl(3S)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-3-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(13 mg, 0.026 mmol) was stirred in methylene chloride (100 μL, 2 mmol)with N,N-diisopropylethylamine (14 L, 0.079 mmol) and cooled to 0° C.Methanesulfonyl chloride (2.6 μL, 0.034 mmol) was added, and the mixturewas stirred at 0° C. for 1 hr. The mixture was evaporated and dilutedwith methanol. The reactions were purified by prep HPLC on C-18 columneluting water:acetonitrile gradient buffered pH 10 to give twoenantiomers: Peak #1 (Example 35): LCMS calculated for C₁₉H₂₃ClFN₆O₃S(M+H)⁺: m/z=469.1; found: 469.1; Peak #2 (Example 36): LCMS calculatedfor C₁₉H₂₃ClFN₆O₃S (M+H)⁺: m/z=469.1; found: 469.1.

Examples 37, 38, 39, and 40.1-{1-[7-Chloro-6-fluoro-2-methyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

The title compound was prepared by methods analogous to Example 36, butusing tert-butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylatein step 2. The reactions were purified by prep HPLC on C-18 columneluting water:acetonitrile gradient buffered pH 10 to give twodiastereomers: Peak #1, which was separated into the respective twoenantiomers by chiral prep HPLC using a Phenomenex Lux Cellulose C-4column 5 μm, 21.2×250 mm eluting 45% ethanol in hexanes at 18 mL/min,with 4 mg/mL loading to give two peaks: Peak #1A (Example 37), retentiontime 9.80 min: LCMS calculated for C₁₉H₂₃ClFN₆O₃S (M+H)⁺: m/z=469.1.found: 469.1; ¹H NMR (300 MHz, DMSO): δ 8.11 (s, 1H), 7.35 (m, 1H), 6.24(m, 1H), 4.75 (m, 1H), 4.21 (m, 2H), 3.78 (m, 1H), 3.39 (m, 1H), 2.87(s, 3H), 2.55 (s, 3H), 1.68 (m, 3H), 1.39 (m, 3H); Peak #1B (Example38), retention time 11.75 min: LCMS calculated for C₁₉H₂₃ClFN₆O₃S(M+H)⁺: m/z=469.1; found: 469.1.

The second diasteromer peak (Peak #2) was separated into the respectivetwo enantiomers by chiral prep HPLC using a Phenomenex Lux Cellulose C-1column 5 μm, 21.2×250 mm eluting 20% ethanol in hexanes at 18 mL/min,with 7 mg/mL loading to give two peaks: Peak #2A (Example 39), retentiontime 12.78 min: LCMS calculated for C₁₉H₂₃ClFN₆O₃S (M+H)⁺: m/z=469.1;found: 469.1; Peak #2B (Example 40), retention time 15.47 min: LCMScalculated for C₁₉H₂₃ClFN₆O₃S (M+H)⁺: m/z=469.1; found: 469.1.

Examples 41 and 42.3-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutanecarboxylicacid trifluoroacetate

The title compound was prepared by methods analogous to Example 26, butusing 3-oxocyclobutanecarboxylic acid in step 2. The reactions werepurified by prep HPLC on C-18 column eluting water:acetonitrile gradientbuffered pH 2 to give two diastereomers: Peak #1 (Example 41): LCMScalculated for C₂₃H₂₇ClFN₆O₃ (M+H)⁺: m/z=489.2; found: 489.2; Peak #2(Example 42): LCMS calculated for C₂₃H₂₇ClFN₆O₃ (M+H)⁺: m/z=489.2;found: 489.2. ¹H NMR (300 MHz, DMSO-d₆): δ 8.11 (s, 1H), 7.60 (m, 1H),6.28 (m, 1H), 4.22 (m, 3H), 4.00 (m, 2H), 3.38 (m, 2H), 2.80 (m, 2H),2.55 (s, 3H), 2.22 (m, 2H), 1.72 (m, 3H), 1.40 (m, 3H).

Examples 43 and 44.3-[(2S)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutanecarboxamide

N,N-Diisopropylethylamine (78 μl, 0.45 mmol) was added to a mixture of3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutanecarboxylicacid trifluoroacetate (44 mg, 0.09 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (34 mg, 0.09 mmol) in N,N-dimethylformamide (2 mL)at room temperature. A solution of ammonia in ethanol (2.0 M, 130 μl)was added and the reaction was stirred at room temperature for 1.5 hrs.The reactions were purified by prep HPLC on C-18 column elutingwater:acetonitrile gradient buffered pH 10 to give two diastereomers:Peak #1 (Example 43): LCMS calculated for C₂₃H₂₈ClFN₇O₂ (M+H)⁺:m/z=488.2; found: 488.2; Peak #2 (Example 44): LCMS calculated forC₂₃H₂₈ClFN₇O₂ (M+H)⁺: m/z=488.2; found: 488.2.

Example 45.1-{1-[8-Chloro-7-fluoro-5-(methylsulfonyl)-3,4,5,6-tetrahydro-2H-1,5-benzoxazocin-10-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Step 1. tert-butyl10-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-8-chloro-7-fluoro-3,4-dihydro-2H-1,5-benzoxazocine-5(6H)-carboxylate

The title compound was prepared by methods analogous to Example 1, steps1-8, but using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone(from Examples 26-27, step 2) and tert-butyl (3-hydroxypropyl)carbamate[Aldrich #416444] in Step 1. LCMS calculated for C₂₃H₂₉ClFN₆O₃ (M+H)⁺:m/z=491.2; found: 491.2.

Step 2.1-{1-[8-Chloro-7-fluoro-5-(methylsulfonyl)-3,4,5,6-tetrahydro-2H-1,5-benzoxazocin-10-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

tert-Butyl10-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-8-chloro-7-fluoro-3,4-dihydro-2H-1,5-benzoxazocine-5(6H)-carboxylate(8 mg, 0.02 mmol) was stirred in methylene chloride (80 μL, 1 mmol) withN,N-diisopropylethylamine (8.5 μL, 0.049 mmol) and cooled to 0° C.Methanesulfonyl chloride (1.6 μL, 0.021 mmol) was added and the mixturewas stirred at 0° C. for 1 hr. The mixture was evaporated and dilutedwith methanol and purified by preparative LCMS (pH 10) to give Example45. LCMS calculated for C₁₉H₂₃ClFN₆O₃S (M+H)⁺: m/z=469.1; found: 469.1.¹H NMR (300 MHz, CD₃OD): δ 8.14 (s, 1H), 7.65 (m, 1H), 6.36 (m, 1H),4.58 (m, 2H), 4.21 (m, 2H), 3.52 (m, 2H), 2.87 (s, 3H), 2.60 (s, 3H),1.91 (m, 2H), 1.80 (m, 3H).

Example 46.4-(1-Acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

Step 1. 1-(4-bromo-5-chloro-2-hydroxyphenyl)ethanone

The 2-bromo-1-chloro-4-methoxybenzene (25.0 g, 113 mmol) [Oakwoodcat#035670] was dissolved in carbon disulfide (250 mL), and the acetylchloride (12 mL, 170 mmol) and aluminum trichloride (37.6 g, 282 mmol)were added. The reaction was heated to reflux and monitored by LC/MS.After heating for 1 h, the reaction became two layers. The reactionallowed to cool to room temperature and poured over ice. The slurry wasextracted with ethyl acetate 3×, the combined organic layer was washedwith brine, dried over magnesium sulfate and concentrated to give1-(4-bromo-5-chloro-2-hydroxyphenyl)ethanone as a solid (28.0 g, 99%).¹H NMR (300 MHz, CDCl₃) δ 12.12 (s, 1H), 7.78 (s, 1H), 7.31 (s, 1H),2.62 (s, 3H).

Step 2. 4-acetyl-2-chloro-5-hydroxybenzonitrile

1-(4-bromo-5-chloro-2-hydroxyphenyl)ethanone (6.2 g, 25 mmol) wascombined with zinc cyanide (4.4 g, 37 mmol) in N,N-dimethylformamide (40mL) degassed with nitrogen and tris(dibenzylideneacetone)dipalladium(0)(0.38 g, 0.42 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.57 g, 0.99mmol) were added. The reaction was degassed with nitrogen and heated to120° C. and monitored by LC/MS. After heating for 2 hrs, the reactionwas allowed to cool to room temperature, diluted with ethyl acetate, andfiltered to remove the solids. The organic layer was washed with water,brine, dried over magnesium sulfate and concentrated in vacuo to givethe crude product. The product was purified by FCC on silica gel elutinghexane:ethyl acetate gradient to give4-acetyl-2-chloro-5-hydroxybenzonitrile as a yellow crystalline solid(3.5 g, 72%).

Step 3. 4-acetyl-6-chloro-3-hydroxy-2-iodobenzonitrile

The 4-acetyl-2-chloro-5-hydroxybenzonitrile (4.9 g, 25 mmol) wasdissolved in acetic acid (61.2 mL), and the N-iodosuccinimide (6.8 g, 30mmol) was added. The reaction was heated to 80° C. and, after heatingfor 18 hrs, the reaction was concentrated in vacuo to remove the aceticacid. The residue was taken up in ethyl acetate, washed with sodiumbicarbonate water, brine, dried over magnesium sulfate and concentratedto give a dark oil. The crude product was purified by FCC on silica geleluting hexane:ethyl acetate gradient to give4-acetyl-6-chloro-3-hydroxy-2-iodobenzonitrile as a yellow solid (5.3 g,66%).

Step 4. tert-butyl[2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)ethyl]carbamate

Diethyl azodicarboxylate (2.3 mL, 14 mmol) was added slowly to asolution of triphenylphosphine (3.79 g, 14.5 mmol) and tert-butyl(2-hydroxyethyl)carbamate (2.3 g, 14 mmol) in tetrahydrofuran (93 mL)and cooled in an ice bath. After stirring for 15 minutes, the4-acetyl-6-chloro-3-hydroxy-2-iodobenzonitrile (3.1 g, 9.6 mmol) wasadded. The reaction was allowed to warm to room temperature and stirredovernight. The reaction was diluted with ethyl acetate and washed withwater, 1 N HCl, and brine, then dried over magnesium sulfate andconcentrated to give a dark oil. The product was purified by FCC onsilica gel eluting hexane: ethyl acetate gradient to give tert-butyl[2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)ethyl]carbamate as a tansolid (3.2 g, 71%). LCMS calculated for C₁₆H₁₈ClIN₂O₄Na (M+Na)⁺:m/z=487.1; found: 486.9.

Step 5. tert-butyl[2-(6-acetyl-4-chloro-3-cyano-2-vinylphenoxy)ethyl]carbamate

A mixture of tert-butyl[2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)ethyl]carbamate (3.3 g, 7.1mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.81 mL, 10.6mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (0.3 g, 0.4 mmol) and potassiumcarbonate (2.9 g, 21 mmol) in 1,4-dioxane (40 mL) and water (20 mL) wasdegassed with nitrogen. The resulting mixture was heated at 80° C. for 1h. The mixture was poured into water and extracted with ethyl acetate.The extracts were washed with brine, dried over magnesium sulfate,filtered and concentrated. The product was purified by FCC on silica gelusing ethyl acetate in hexane (0-40%) to give the desired compoundtert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-vinylphenoxy)ethyl]carbamateas a crystalline solid (2.2 g. 85%). LCMS calculated for C₁₈H₂₁ClIN₂O₄Na(M+Na)⁺: m/z=387.1; found: 387.0.

Step 6. tert-butyl{2-[4-chloro-3-cyano-6-(1-hydroxyethyl)-2-vinylphenoxy]ethyl}carbamate

Tert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-vinylphenoxy)ethyl]carbamate(1.6 g, 4.4 mmol) was dissolved in methanol (40 mL) cooled in an icebath and the sodium tetrahydroborate (0.16 g, 4.4 mmol) was added. Thereaction was stirred for 1 h and water was added to quench residualhydride and the reaction was concentrated to remove the methanol. Theaqueous was diluted with ethyl acetate washed with brine, dried overmagnesium sulfate and concentrated to give tert-butyl{2-[4-chloro-3-cyano-6-(1-hydroxyethyl)-2-vinylphenoxy]ethyl}carbamateas a glass (1.6 g, 100%). LCMS calculated for C₁₈H₂₃ClN₂O₄Na (M+Na)⁺:m/z=389.1; found: 389.1.

Step 7. tert-butyl{2-[4-chloro-3-cyano-2-formyl-6-(1-hydroxyethyl)phenoxy]ethyl}carbamate

Tert-butyl{2-[4-chloro-3-cyano-6-(1-hydroxyethyl)-2-vinylphenoxy]ethyl}carbamate(1.6 g, 4.4 mmol) was dissolved in methylene chloride (1.2 mL) cooled ina dry ice acetone bath and ozone/oxygen was bubbled through the solutionuntil a persistent blue color remained. The reaction was purged withoxygen and nitrogen to remove excess ozone and dimethyl sulfide (0.80mL, 11 mmol) was added to reduce the ozonide. After stirring for 1 h,the reaction was complete. This was concentrated in vacuo to give aresidue give tert-butyl{2-[4-chloro-3-cyano-2-formyl-6-(1-hydroxyethyl)phenoxy]ethyl}carbamate.LCMS calculated for Cl₇H₂₁ClN₂O₅Na (M+Na)⁺: m/z=391.1; found: 391.1.

Step 8.7-chloro-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-6-carbonitrile

The crude tert-butyl{2-[4-chloro-3-cyano-2-formyl-6-(1-hydroxyethyl)phenoxy]ethyl}carbamatewas dissolved in 1,4-dioxane (16 mL) and was added to an ice cooled 4.0M hydrogen chloride in dioxane (40 mL) solution. After stirring for 1 h,the reaction was concentrated in vacuo to give7-chloro-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-6-carbonitrileas an oil. LCMS calculated for C₁₂H₁₂ClN₂O₂ (M+H)⁺: m/z=251.1; found:251.0. ¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (t, J=2.0 Hz, 1H), 7.75 (s, 1H),5.53 (d, J=4.6 Hz, 1H), 5.05-4.82 (m, 1H), 4.53-4.24 (m, 2H), 4.20-4.04(m, 2H), 1.26 (d, J=6.4 Hz, 3H).

Step 9.7-chloro-9-(1-hydroxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

The crude7-chloro-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-6-carbonitrilewas taken up in ethanol (30 mL) cooled in an ice bath and the sodiumtetrahydroborate (0.16 g, 4.4 mmol) was added. The reaction was allowedto stir for 1 h, and water was added to quench the remaining hydride andthe reaction was concentrated to remove most of the ethanol. The residuewas dissolved with ethyl acetate, washed with brine, dried overmagnesium sulfate, and concentrated to give7-chloro-9-(1-hydroxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrileas an oil (0.45 g, 41%). LCMS calculated for C₁₂H₁₄ClN₂O₂ (M+H)⁺:m/z=253.1. found: 253.0.

Step 10. tert-butyl7-chloro-6-cyano-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

7-Chloro-9-(1-hydroxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile(0.140 g, 0.554 mmol) was dissolved in methylene chloride (5.0 mL, 78mmol) and N,N-diisopropylethylamine (0.29 mL, 1.7 mmol) at roomtemperature, and the di-tert-butyldicarbonate (0.24 g, 1.1 mmol) wasadded. The reaction was stirred at room temperature for 1 hr and thendiluted with ethyl acetate and washed with 1 N HCl, brine, dried overmagnesium sulfate, and concentrated to give a yellow oil. The productwas purified by FCC on silica gel eluting a hexane:ethyl acetategradient to give tert-butyl7-chloro-6-cyano-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylateas an oil (0.12 g, 61%). LCMS calculated for C₁₇H₂₁ClN₂O₄Na (M+Na)⁺:m/z=375.1; found: 375.0.

Step 11. tert-butyl7-chloro-9-(1-chloroethyl)-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

The tert-butyl7-chloro-6-cyano-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(0.090 g, 0.26 mmol) was dissolved in methylene chloride (3 mL) andN,N-dimethylformamide (0.020 mL) and cooled in an ice bath. The thionylchloride (0.037 mL, 0.51 mmol) was added slowly, and the reaction wasstirred for 1 h and then diluted with methylene chloride (30 mL). Thereaction mixture was cooled in an ice bath, and water saturated sodiumbicarbonate was added. The organic layer was washed with water, brine,dried over magnesium sulfate, and concentrated to give tert-butyl7-chloro-9-(1-chloroethyl)-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylateas an oil. LCMS calculated for C₁₇H₂₀Cl₂N₂O₃Na (M+Na)⁺: m/z=393.1;found: 393.0.

Step 12. tert-butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

The crude tert-butyl7-chloro-9-(1-chloroethyl)-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate(0.090 g, 0.26 mmol) was dissolved in N,N-dimethylformamide (3 mL), and3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.076 g, 0.51 mmol) andcesium carbonate (0.17 g, 0.51 mmol) were added. The reaction was heatedto 90° C. for 18 hrs and then allowed to cool to room temperature. Thereaction was diluted with ethyl acetate and then decanted from thesolids. The organic layer was washed with water, brine, dried overmagnesium sulfate, and concentrated to give tert-butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylateas an oil. LCMS calculated for C₂₃H₂₇ClN₇O₃ (M+H)⁺: m/z=484.1; found:484.1.

Step 13.9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrilebishydrochloride

The crude tert-butyl9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylatewas dissolved in 4.0 M hydrogen chloride in dioxane (4.0 mL) at roomtemperature and was stirred for 1 h. The reaction was concentrated invacuo to give9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrilebishydrochloride as an off white solid (0.065 g, 66%). LCMS calculatedfor C₁₈H₁₉ClN₇O (M+H)⁺: m/z=384.1; found: 384.2.

Step 14. tert-butyl3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate

9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrilebishydrochloride (0.030 g, 0.078 mmol) was dissolved in methanol (3.0mL), and the tert-butyl 3-oxoazetidine-1-carboxylate (0.027 g, 0.16mmol) and then sodium cyanoborohydride (0.0098 g, 0.16 mmol) were added.The reaction was heated to 60° C. for 3 hrs and then allowed to cool toroom temperature. The reaction was diluted with ethyl acetate and washedwith brine. The organic layer dried over magnesium sulfate andconcentrated to give the crude product as an amber oil. The oil waspurified by prep HPLC on a C-18 column eluting water:acetonitrilegradient at pH 10 to give tert-butyl3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate(0.015 g, 35%). LCMS calculated for C₂₆H₃₂ClN₈O₃ (M+H)⁺: m/z=539.2;found: 539.2.

Step 15.9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitriletrishydrochloride

Tert-butyl3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate(0.015 g, 0.0278 mmol) was dissolved in 4.0 M hydrogen chloride indioxane (3.0 mL, 12 mmol) at room temperature and stirred for 1 hr andthen concentrated in vacuo to give9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitriletrishydrochloride as a semi-solid. LCMS calculated for C₂₁H₂₄ClN₈O(M+H)⁺: m/z=439.1; found: 439.1.

Step 16.4-(1-acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

The crude9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitriletrishydrochloride (0.015 g, 0.0278 mmol) was dissolved inN,N-dimethylformamide (2 mL) and cooled in an ice bath, and thenN,N-diisopropylethylamine (0.0142 g, 0.112 mmol) and acetic anhydride(0.0032 mL, 0.033 mmol) were added. After stirring for 1 h, the productwas purified without work up, by prep HPLC on a C-18 column elutingwater:acetonitrile gradient buffered pH 10 to give4-(1-acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrileas a white amorphous solid (0.004 g, 33%). LCMS calculated forC₂₃H₂₆ClN₈O₂ (M+H)⁺: m/z=481.2; found: 481.2.

Example 47.9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-[1-(2-hydroxyethyl)azetidin-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile(0.015 g, 0.034 mmol) (from Example 46, Step 15) and 2-bromoethanol(0.0097 mL, 0.14 mmol) were combined in N,N-dimethylformamide (1 mL)with triethylamine (0.019 mL, 0.14 mmol) at room temperature. Thereaction was heated to 85° C. and after heating for 2 hrs the reactionwas concentrated in vacuo and the residue was purified by prep HPLC on aC-18 column eluting water:acetonitrile gradient buffered pH 10 to givethe desired compound as a white amorphous solid (0.008 g, 50%). LCMScalculated for C₂₃H₂₈ClN₈O₂ (M+H)⁺: m/z=483.2; found: 483.2.

Examples 48 and 49.4-(1-Acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

Step 1. tert-butyl[2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)propyl]carbamate

Using methods analogous to Example 46, but using tert-butyl(2-hydroxypropyl)carbamate in step 4, tert-butyl[2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)propyl]carbamate wasprepared as a pale yellow oil (1.3 g, 58%). LCMS calculated forC₁₇H₂₀ClN₂O₄Na (M+Na)⁺: m/z=501.0; found: 501.0.

Step 2.4-(1-acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

Using methods analogous to Example 46, but using the intermediatetert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)propyl]carbamate,the desired compound was prepared as a mixture of diastereomers. Theisomers were separated and purified by prep HPLC on a C-18 columneluting water:acetonitrile gradient buffered pH 10, to obtain: Peak #1(Example 48): LCMS calculated for C₂₄H₂₈ClN₈O₂ (M+H)⁺: m/z=495.1; found:495.2. and Peak #2 (Example 49): LCMS calculated for C₂₄H₂₈ClN₈O₂(M+H)⁺: m/z=495.1; found: 495.2.

Examples 50 and 51.2-{3-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidin-1-yl}acetamide

Step 1.9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitriletrishydrochloride

Using methods analogous to Example 46, steps 1-15, but using tert-butyl(2-hydroxypropyl)carbamate in step 4, the9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitriletrishydrochloride was prepared as a solid. LCMS calculated forC₂₂H₂₆ClN₈O (M+H)⁺: m/z=453.2; found: 453.2.

Step 2.2-{3-[9-[1-(4-amino-3-methyl-H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidin-1-yl}acetamide

2-Bromoacetamide (0.01 g, 0.09 mmol) was added to a mixture of9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitriletrishydrochloride (20 mg, 0.04 mmol) and triethylamine (20 μL, 0.18mmol) in N,N-dimethylformamide (2 mL) and then heated to 80° C. for 2 h.The reaction was allowed to cool and was purified without work up byprep HPLC on a C-18 column eluting water:acetonitrile gradient bufferedpH 10 to give the title compounds as two separated diastereomers: Peak#1 (Example 50): LCMS calculated for C₂₄H₂₉ClN₉O₂ (M+H)⁺: m/z=510.2;found: 510.2; Peak #2 (Example 51): LCMS calculated for C₂₄H₂₉ClN₉O₂(M+H)⁺: m/z=510.2; found: 510.2.

Examples 52 and 53.2-{3-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidin-1-yl}acetamide

Peak #2 (from Example 51) was separated into the respective enantiomersby chiral prep HPLC using a Phenomenex Lux Cellulose C-4 column 5 μm,21.2×250 mm eluting with 60% ethanol in hexanes at 18 mL/min, with 5mg/mL loading to give two peaks: Peak #1 (Example 52), retention time9.48 min: LCMS calculated for C₂₄H₂₉ClN₉O₂ (M+H)⁺: m/z=510.2; found:510.2; Peak #2 (Example 53), retention time 12.42 min: LCMS calculatedfor C₂₄H₂₉ClN₉O₂ (M+H)⁺: m/z=510.2; found: 510.2.

Examples 54 and 55.9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-[1-(2-hydroxy-2-methylpropyl)azetidin-3-yl]-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitriletrishydrochloride (0.015 g, 0.034 mmol) was dissolved inN,N-dimethylformamide (1.0 mL) and triethylamine (0.025 mL, 0.18 mmol),and 2,2-dimethyloxirane (0.050 g) was added. The reaction was heated to85° C. stirred for 4 h. The reaction was concentrated in vacuo, and theproduct was purified without workup by prep HPLC on a C-18 columneluting water:acetonitrile gradient buffered pH 10 to give the titlecompound as two diastereomers: Peak #1 (Example 54) (0.002 g, 13%): LCMScalculated for C₂₆H₃₄ClN₈O₂ (M+H)⁺: m/z=525.2; found: 525.2; Peak #2(Example 55) (0.002 g 13%): LCMS calculated for C₂₆H₃₄ClN₈O₂ (M+H)⁺:m/z=525.2; found: 525.2.

Examples 56 and 57.(2S)-9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-[1-(2-hydroxyethyl)azetidin-3-yl]-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

Using methods analogous to Example 47, but using tert-butyl[(2R)-2-hydroxypropyl]carbamate (from Example 46, step 4), the desiredproducts were prepared as a mixture of single diastereomers. Thereaction products were purified by prep HPLC on a C-18 column elutingwater:acetonitrile gradient buffered pH 10 to give two diastereomers:Peak #1 (Example 56), as a white amorphous solid: LCMS calculated forC₂₄H₃₀ClN₈O₂ (M+H)⁺: m/z=497.2; Found: 497.2; Peak #2 (Example 57), as awhite amorphous solid: LCMS calculated for C₂₄H₃₀ClN₈O₂ (M+H)⁺:m/z=497.2; found: 497.2.

Example 58.9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

2-Bromoethanol (4.7 μL, 0.066 mmol) was added to a mixture of9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrilebishydrochloride (15 mg, 0.039 mmol) (from Example 46, step 13) andtriethylamine (10 μL, 0.09 mmol) in N,N-dimethylformamide (2 mL). Thereaction was heated at 80° C. for 3 h and then allowed to cool. Theproduct was purified without workup by prep HPLC on a C-18 columneluting water:acetonitrile gradient buffered pH 10 to give the desiredcompound as white amorphous solid (0.08 g, 50%). LCMS calculated forC₂₀H₂₃ClN₇O₂ (M+H)⁺: m/z=428.1; found: 428.2.

Examples 59 and 60.9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-4-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

Step 1.9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrilebishydrochloride

Using methods analogous to Example 46, steps 1-13, but using tert-butyl(2-hydroxypropyl)carbamate in step 4, the9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrilebishydrochloride was prepared as a mixture of diastereomers. LCMScalculated for C₁₉H₂₁ClN₇O (M+H)⁺: m/z=398.1; found: 398.2.

Step 2.9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-4-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrilebishydrochloride (0.020 g, 0.05 mmol) was taken up inN,N-dimethylformamide (2.0 mL) and triethylamine (0.034 mL, 0.24 mmol),and the 3-(bromomethyl)pyridine hydrobromide was added. The reaction washeated to 85° C. for 2 h and was allowed to cool. The product waspurified by prep HPLC on C-18 column eluting water:acetonitrile gradientbuffered pH 10 to give two diastereomers: Peak #1 (Example 59): LCMScalculated for C₂₅H₂₆ClN₈O (M+H)⁺: m/z=489.2; found: 489.2; Peak #2(Example 60): LCMS calculated for C₂₅H₂₆ClN₈O (M+H)⁺: m/z=489.2; found:489.2.

Examples 61, 62, 63, and 64.9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-(2-hydroxyethyl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

Using methods analogous to Example 59, but using 2-bromoethanol in step2, a mixture of diastereomers of the desired compound was prepared. Theisomers were separated into the respective four enantiomers by chiralprep HPLC using a Phenomenex Lux Cellulose C-4 column 5 μm, 21.2×250 mmeluting 20% ethanol in hexanes at 22 mL/min, with 7 mg/mL loading togive four peaks retention time: Peak #1 (Example 61), retention time15.47 min: LCMS calculated for C₂₁H₂₅ClN₇O₂ (M+H)⁺: m/z=442.2; found:442.1; Peak #2 (Example 62), retention time 18.18 min: LCMS calculatedfor C₂₁H₂₅ClN₇O₂ (M+H)⁺: m/z=442.2; found: 442.1; Peak #3 (Example 63),retention time 26.86 min: LCMS calculated for C₂₁H₂₅ClN₇O₂ (M+H)⁺:m/z=442.2; found: 442.1; Peak #4 (Example 64), retention time 29.28 min:LCMS calculated for C₂₁H₂₅ClN₇O₂ (M+H)⁺: m/z=442.2; found: 442.1.

Examples 65 and 66.9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-(2-hydroxy-2-methylpropyl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

Oxirane, 2,2-dimethyl-(5.5 μL, 0.066 mmol) was added to a mixture of9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrilebishydrochloride (16 mg, 0.039 mmol) and triethylamine (10 μL, 0.09mmol) in N,N-dimethylformamide (2 mL). The reaction was heated at 80° C.for 3 hrs and was allowed to cool to room temperature. The reaction waspurified without workup by prep HPLC on C-18 column elutingwater:acetonitrile gradient buffered pH 10 to give two diastereomers:Peak #1 (Example 65): LCMS calculated for C₂₃H₂₉ClN₇O₂ (M+H)⁺:m/z=470.2; found: 470.2; Peak #2 (Example 66): LCMS calculated forC₂₃H₂₉ClN₇O₂ (M+H)⁺: m/z=470.2; found: 470.2.

Examples 67 and 68.N-{3-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutyl}acetamide

Step 1: tert-Butyl{3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutyl}carbamate

9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrilebishydrochloride (20 mg, 0.05 mmol) from Example 59, step 1, wasdissolved in methanol (1.1 mL), and the tert-butyl(3-oxocyclobutyl)carbamate (0.019 g, 0.10 mmol) was added, followed bythe sodium cyanoborohydride (0.0063 g, 0.10 mmol). The reaction washeated to 60° C. for 2 h, allowed to cool, diluted with water, andextracted with ethyl acetate. The combined organic layer was washed withbrine, dried over magnesium sulfate, filtered, and concentrated to givetert-butyl{3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutyl}carbamate.LCMS calculated for C₂₈H₃₆ClN₈O₃ (M+H)⁺: m/z=567.2; found: 567.3.

Step 2.4-(3-Aminocyclobutyl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitriletris hydrochloride

Tert-butyl{(3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutyl}carbamatewas taken up in 4.0 M hydrogen chloride in dioxane (1 mL, 4 mmol) andwas stirred for 1 h. The reaction was concentrated in vacuo to givecrude4-(3-aminocyclobutyl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitriletrishydrochloride as a solid. LCMS calculated for C₂₃H₂₈ClN₈O (M+H)⁺:m/z=467.2; found: 467.2.

Step 3.N-{3-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutyl}acetamide

The crude4-(3-aminocyclobutyl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitriletrishydrochloride was dissolved in N,N-dimethylformamide (2 mL) andtriethylamine (10 μL, 0.1 mmol). To this mixture was added aceticanhydride (7.7 mg, 0.075 mmol). The reaction was stirred for 1 h at roomtemperature, and the reaction was purified without workup by prep HPLCon C-18 column eluting water:acetonitrile gradient buffered pH 10 togive two diastereomers: Peak #1 (Example 67): LCMS calculated forC₂₅H₃₀ClN₈O₂ (M+H)⁺: m/z=509.2; found: 509.2; Peak #2 (Example 68): LCMScalculated for C₂₅H₃₀ClN₈O₂ (M+H)⁺: m/z=509.2; found: 509.2.

Examples 69 and 70.9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-ethyl-4-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

Step 1. tert-Butyl (2-hydroxybutyl)carbamate

Di-tert-butyldicarbonate (3.7 g, 17 mmol) was added to a solution of1-amino-2-butanol (1 g, 10 mmol) and N,N-diisopropylethylamine (3 g, 20mmol) in methylene chloride (20 mL). The reaction was stirred for 3 h atroom temperature and was partitioned between methylene chloride andwater. The combined organic layer was washed with 1 N HCl, brine, driedover MgSO₄, filtered and concentrated to give crude tert-butyl(2-hydroxybutyl)carbamate (2.0 g, 90%).

Step 2,9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-ethyl-4-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile

Using methods analogous to Example 61, but using tert-butyl(2-hydroxybutyl)carbamate, the title compound was prepared as a mixtureof diastereomers. The reaction was purified by prep HPLC on C-18 columneluting water:acetonitrile gradient buffered pH 10 to give twodiastereomers. Peak #1 (Example 69): LCMS calculated for C₂₂H₂₇ClN₇O₂(M+H)⁺: m/z=456.2; Found: 456.2; Peak #2 (Example 70): LCMS calculatedfor C₂₂H₂₇ClN₇O₂ (M+H)⁺: m/z=456.2; Found: 456.2.

Examples 71 and 72.4-(1-Acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-4,5-dihydro-1,4-benzoxazepin-3(2H)-one

Step 1. Ethyl 2-(6-acetyl-4-chloro-3-fluoro-2-iodophenoxy)propanoate

A solution of 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (5.00g, 15.9 mmol) in N,N-dimethylformamide (80.0 mL) was treated withpotassium carbonate (4.39 g, 31.8 mmol), followed by ethyl2-bromopropanoate (2.48 mL, 19.1 mmol), and then stirred at 60° C. for 3h. The reaction was stirred overnight at 60° C., and then worked up perthe procedure below. The reaction was then re-submitted to the reactionconditions and stirred at 90° C. for 4 h. The reaction mixture wasdiluted with water and ethyl acetate. The organic layer was separatedand washed with brine, dried over magnesium sulfate, filtered, andconcentrated to give a crude residue. Purification by flash columnchromatography (100% hexanes to 10% EtOAc/hexanes) gave the desiredproduct (3.66 g, 56%) as a mixture of enantiomers. LCMS calculated forC₁₃H₁₄ClFIO₄ (M+H)⁺: m/z=415.0; found: 414.9.

Step 2. Ethyl 2-[4-chloro-3-fluoro-2-iodo-6-(2-methyl-1,3-dioxolan-2-yl)phenoxy]propanoate

A solution of ethyl2-(6-acetyl-4-chloro-3-fluoro-2-iodophenoxy)propanoate (3.58 g, 8.63mmol) and 1,2-ethanediol (1.20 mL, 21.6 mmol) in toluene (16.3 mL) wastreated with p-toluenesulfonic acid monohydrate (246 mg, 1.30 mmol) andheated at reflux in a flask fitted with a Dean-Stark trap filled withsieves. The reaction mixture was cooled and poured into saturated sodiumbicarbonate (150 mL) and extracted with ethyl acetate (2×200 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated to give a crude residue.Purification by flash column chromatography (100% hexanes to 10%EtOAc/hexanes) gave the desired product (2.25 g, 57%) as a mixture ofenantiomers. LCMS calculated for C₁₅H₁₈ClFIO₅ (M+H)⁺: m/z=459.0; found:459.0.

Step 3. Ethyl 2-[4-chloro-3-fluoro-6-(2-methyl-1,3-dioxolan-2-yl)-2-vinylphenoxy]propanoate

A mixture of ethyl2-[4-chloro-3-fluoro-2-iodo-6-(2-methyl-1,3-dioxolan-2-yl)phenoxy]propanoate(1.83 g, 3.99 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(0.880 mL, 5.19 mmol), and potassium carbonate (1.65 g, 12.0 mmol) in1,4-dioxane (15.6 mL) and water (7.8 mL) was degassed with nitrogen for10 min. The reaction mixture was treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (163 mg, 0.199 mmol), degassed with nitrogen foranother 10 min, and heated at 80° C. for 2 h. The reaction mixture wasfiltered through Celite and washed with ethyl acetate. The filtrate waspoured into water. The aqueous layer was separated and re-extracted withethyl acetate. The combined organic extracts were washed with brine,dried over sodium sulfate, filtered, and concentrated give a cruderesidue. Purification by flash column chromatography (100% hexanes to15% EtOAc/hexanes) gave the desired product (2.25 g, 57%) as a mixtureof enantiomers. LCMS calculated for C₁₇H₂₁ClFO₅ (M+H)⁺: m/z=359.1;found: 359.1.

Step 4. Ethyl 2-[4-chloro-3-fluoro-2-formyl-6-(2-methyl-1,3-dioxolan-2-yl)phenoxy]propanoate

A solution of ethyl2-[4-chloro-3-fluoro-6-(2-methyl-1,3-dioxolan-2-yl)-2-vinylphenoxy]propanoate(400 mg, 1.11 mmol) in methylene chloride (40 mL) at −78° C. was treatedwith ozone until a purple color persisted. The reaction mixture waspurged with oxygen, treated with dimethyl sulfide (1 mL) and warmed toroom temperature. The reaction mixture was concentrated to give thecrude product (392 mg, 98%) as a mixture of enantiomers that was usedwithout further purification. LCMS calculated for C₁₆H₁₉ClFO₆ (M+H)⁺:m/z=361.1. found: 361.1.

Step 5. 1-Acetylazetidin-3-amine hydrochloride

A solution of tert-butyl azetidin-3-ylcarbamate (1.00 g, 5.81 mmol) [ArkPharma, AK26432] in tetrahydrofuran (50 mL) was treated withtriethylamine (1.6 mL, 11.6 mmol) followed by N,N-dimethylformamide (15mL) and cooled to 0° C. The reaction mixture was treated with acetylchloride (495 μL, 6.97 mmol) and stirred overnight at room temperature.The reaction mixture was diluted with ether and washed with water andbrine, dried over magnesium sulfate, filtered, and concentrated give acrude residue that was used immediately without purification. Theintermediate azetidine was diluted with methylene chloride (30 mL),treated with 4.0 M hydrogen chloride in dioxane (22.0 mL, 88.0 mmol),and stirred at rt for 30 min. The reaction mixture was diluted withether and the precipitated solid was collected by filtration in order togive the desired product (550 mg, 63%) as a HCl salt. LCMS calculatedfor C₅H₁₁N₂O (M+H)⁺: m/z=115.1; found: 115.2.

Step 6.4-(1-Acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-9-(2-methyl-1,3-dioxolan-2-yl)-4, 5-dihydro-1,4-benzoxazepin-3 (2H)-one

A solution of ethyl2-[4-chloro-3-fluoro-2-formyl-6-(2-methyl-1,3-dioxolan-2-yl)phenoxy]propanoate(392 mg, 1.09 mmol) in methanol (21 mL) was treated with sodiumcyanoborohydride (171 mg, 2.72 mmol) followed by1-acetylazetidin-3-amine hydrochloride (360 mg, 2.39 mmol) and stirredat room temperature overnight. The reaction mixture was quenched withacetic acid (200 μL) and concentrated in vacuo. The residue was dilutedwith toluene (60 mL) and heated at 110° C. for 2 h. The solvent wasconcentrated in vacuo, and the residue was purified via preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to givethe desired product (142 mg, 32%) as a mixture of enantiomers. LCMScalculated for C₁₉H₂₃ClFN₂O₅ (M+H)⁺: m/z=413.1; found: 413.1.

Step 7. 9-Acetyl-4-(1-acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-4,5-dihydro-1,4-benzoxazepin-3(2H)-one

A solution of4-(1-acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-9-(2-methyl-1,3-dioxolan-2-yl)-4,5-dihydro-1,4-benzoxazepin-3(2H)-one(190 mg, 0.460 mmol) in methanol (20 mL) and was treated with 6.0 Mhydrogen chloride in water (1.15 mL, 6.90 mmol) and stirred at roomtemperature for 3 h. The reaction mixture was diluted with ethyl acetateand water. The organic layer was separated, washed with brine, driedover sodium sulfate, filtered, and concentrated to give the desiredproduct (132 mg, 78%) as a mixture of enantiomers that was used withoutfurther purification. LCMS calculated for C₁₇H₁₉ClFN₂O₄ (M+H)⁺:m/z=369.1. found: 369.1.

Step 8.4-(1-Acetylazetidin-3-yl)-7-chloro-6-fluoro-9-(1-hydroxyethyl)-2-methyl-4,5-dihydro-1, 4-benzoxazepin-3(2H)-one

A solution of9-acetyl-4-(1-acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-4,5-dihydro-1,4-benzoxazepin-3(2H)-one(112 mg, 0.304 mmol) in methanol (5.6 mL) at −10° C. was treated withsodium tetrahydroborate (17 mg, 0.456 mmol) and stirred for 30 min at 0°C. The reaction mixture was quenched with acetic acid (86 μL, 1.52 mmol)at 0° C. and then diluted with ethyl acetate and water. The organiclayer was separated, washed with brine, dried over sodium sulfate,filtered, and concentrated to give a crude residue. Purification viapreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) gave two fractions. Each fraction contained a pair ofenantiomers: peak 1 (30 mg, 27%) and peak 2 (50 mg, 44%). Peak 1: LCMScalculated for C₁₇H₂₁ClFN₂O₄ (M+H)⁺: m/z=371.1; found: 371.1. Peak 2:LCMS calculated for C₁₇H₂₁ClFN₂O₄ (M+H)⁺: m/z=371.1; found: 371.1.

Step 9.4-(1-Acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-4,5-dihydro-1,4-benzoxazepin-3(2H)-one

The two fractions from step 8 were processed individually andidentically. A suspension of4-(1-acetylazetidin-3-yl)-7-chloro-6-fluoro-9-(1-hydroxyethyl)-2-methyl-4,5-dihydro-1,4-benzoxazepin-3(2H)-one(49.0 mg, 0.132 mmol) (step 8, peak 2) and N,N-dimethylformamide (1.0μL, 0.013 mmol) in methylene chloride (1.1 mL) was treated with thionylchloride (24 μL, 0.330 mmol) and stirred for 2 h. The reaction mixturewas added to ice cooled saturated sodium bicarbonate and diluted withdichloromethane. The organic layer was separated, washed with brine,dried over sodium sulfate, filtered, and concentrated to give theintermediate chloride that was used immediately. A solution of thechloro intermediate in N,N-dimethylformamide (2.0 mL) and was treatedwith 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.198 mmol)and cesium carbonate (86.1 mg, 0.264 mmol) and heated in a sealed tubeat 80° C. for 2 h. The reaction mixture was purified via preparativeLCMS (XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to givethe desired product (19 mg, 29%) as a mixture of enantiomers. Productproduced starting from the product of step 8, peak 1 (Example 71): LCMScalculated for C₂₃H₂₆ClFN₇O₃ (M+H)⁺: m/z=502.2; found: 502.1; ¹H NMR(400 MHz, DMSO-d₆) δ 8.20 (s, 0.4H), 8.16 (s, 0.6H), 7.74 (br s, 2H),7.43 (d, J=8.2 Hz, 0.4H), 7.20 (d, J=8.3 Hz, 0.6H), 6.31-6.01 (m, 1H),5.67-5.55 (m, 0.6H), 5.38-5.25 (m, 0.4H), 5.22-5.04 (m, 2H), 4.65-4.48(m, 1H), 4.38-4.26 (m, 0.6H), 4.22-4.13 (m, 0.4H), 4.12-3.97 (m, 1H),3.94-3.79 (m, 1H), 3.74-3.21 (m, 1H), 2.56 (s, 1.8H), 2.53 (s, 1.2H),1.81-1.62 (m, 6H), 1.40 (d, J=6.2 Hz, 1.8H), 1.23-1.13 (m, 1.2H);Product produced starting from the product of step 8, peak 2 (Example72): LCMS calculated for C₂₃H₂₆ClFN₇O₃ (M+H)⁺: m/z=502.2; found: 502.1;¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (s, 0.9H), 8.12 (s, 0.1H), 7.47 (br s,2H), 7.41 (d, J=8.5 Hz, 0.9H), 7.17 (d, J=8.5 Hz, 0.1H), 6.25-6.06 (m,1H), 5.71-5.52 (m, 0.1H), 5.39-5.23 (m, 0.9H), 5.22-5.01 (m, 2H),4.66-4.47 (m, 1H), 4.41-4.25 (m, 0.9H), 4.23-4.12 (m, 0.1H), 4.11-3.96(m, 1H), 3.94-3.77 (m, 1H), 3.67-3.54 (m, 1H), 2.55 (s, 0.3H), 2.52 (s,2.7H), 1.82-1.61 (m, 6H), 1.40 (d, J=6.2 Hz, 0.3H), 1.27-1.16 (m, 2.7H).

Compounds Synthesized

Experimental procedures for compounds below are summarized in Table 1below. Mass spectrometry data and ¹H NMR data for the compounds aresummarized in Table 2.

TABLE 1

Ex. No. Name R^(x) R^(w) R^(3b) R⁴ R⁵ Proc.^(a) 733-[9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2,3- dihydro-1,4-benzoxazepin- 4(5H)-yl]-N,N-dimethylazetidine-1- carboxamide H H

F Cl 34 74 3-[9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7- chloro-6-fluoro-2,3-dihydro-1,4-benzoxazepin- 4(5H)-yl]-N,N- dimethylazetidine-1-sulfonamide H H

F Cl 34 75 1-(1-{7-chloro-6-fluoro-2- methyl-4-[1-(methylsulfonyl)azetidin-3- yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl}ethyl)- 3-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amineMe H

F Cl 28 76 1-{1-[7-chloro-6-fluoro-2- methyl-4-(1-propionylazetidin-3-yl)- 2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}- 3-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amineMe H

F Cl 28 77, 78 (2R)-1-[9-[1-(4-amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7- chloro-6-fluoro-2-methyl- 2,3-dihydro-1,4-benzoxazepin-4(5H)- yl]propan-2-ol Me H

F Cl 50 Peak 1 (Ex. 77) Peak 2 (Ex. 78) 79, 80 methyl3-[9-[1-(4-amino-3- methyl-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl- 2,3-dihydro-1,4- benzoxazepin-4(5H)-yl]azetidine-1-carboxylate Me H

F Cl 28 Peak 1 (Ex. 79) Peak 2 (Ex. 80) 81, 823-[9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl- 2,3-dihydro-1,4- benzoxazepin-4(5H)-yl]azetidine-1-sulfonamide Me

F Cl 28 Peak 1 (Ex. 81) Peak 2 (Ex. 82) 83, 843-[9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl- 2,3-dihydro-1,4- benzoxazepin-4(5H)-yl]azetidine-1-carboxamide Me H

F Cl 28 Peak 1 (Ex. 83) Peak 2 (Ex. 84) 85 (2S)-1-{3-[(2S)-9-[(1S)-1-(4-amino-3-methyl-1H- pyrazolo[3,4-d]pyrimidin- l-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3- dihydro-1,4-benzoxazepin- 4(5H)-yl]azetidin-1-yl}propan-2-ol Me H

F Cl 50 86 (2R)-1-{3-[(2S)-9-[(1S)-1- (4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)ethyl]-7-chloro-6- fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin- 4(5H)-yl]azetidin-1- yl}propan-2-ol Me H

F Cl 50 87, 88 2-{3-[(2S)-9-[1-(4-amino- 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7- chloro-6-fluoro-2-methyl- 2,3-dihydro-1,4-benzoxazepin-4(5H)- yl]azetidin-1-yl}acetamide Me H

F Cl 28 Peak 1 (Ex. 87) Peak 2 (Ex. 88) 89 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7- chloro-4-(1-propionylazetidin-3-yl)- 2,3,4,5-tetrahydro-1,4- benzoxazepine-6-carbonitrile H H

CN Cl 46 90 9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7- chloro-4-[1- (methylsulfonyl)azetidin-3-yl]-2,3,4,5-tetrahydro-1,4- benzoxazepine-6- carbonitrile H H

CN Cl 46 91 3-[9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7- chloro-6-cyano-2,3- dihydro-1,4-benzoxazepin-4(5H)-yl]-N- isopropylazetidine-1- carboxamide H H

CN Cl 46 92 ethyl 3-[9-[1-(4-amino-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7- chloro-6-cyano-2,3- dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1- carboxylate H H

CN Cl 46 93, 94 9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7- chloro-2-methyl-4-[1-(methylsulfonyl)azetidin-3- yl]-2,3,4,5-tetrahydro-1,4- benzoxazepine-6-carbonitrile Me H

CN Cl 48 Peak 1 (Ex. 93) Peak 2 (Ex. 94) 95, 96 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7- chloro-2-methyl-4-(1-propionylazetidin-3-yl)- 2,3,4,5-tetrahydro-1,4- benzoxazepine-6-carbonitrile Me H

CN Cl 48 Peak 1 (Ex. 95) Peak 2 (Ex. 96) 97, 983-[9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl- 2,3-dihydro-1,4- benzoxazepin-4(5H)-yl]-N-ethylazetidine-1- carboxamide Me H

CN Cl 48 Peak 1 (Ex. 97) Peak 2 (Ex. 98)  99, 100 ethyl3-[9-[1-(4-amino-3- methyl-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl- 2,3-dihydro-1,4- benzoxazepin-4(5H)-yl]azetidine-1-carboxylate Me H

CN Cl 48 Peak 1 (Ex. 99) Peak 2 (Ex. 100)  101,  102 3-[9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl- 2,3-dihydro-1,4- benzoxazepin-4(5H)-yl]-N-isopropylazetidine-1- carboxamide Me H

CN Cl 48 Peak 1 (Ex. 101) Peak 2 (Ex. 102)  103,  104 9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-4-[1-(2- hydroxyethyl)azetidin-3- yl]-2-methyl-2,3,4,5-tetrahydro-1,4- benzoxazepine-6- carbonitrile Me H

CN Cl 50 Peak 1 (Ex. 103) Peak 2 (Ex. 104)  105,  106 3-[9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl- 2,3-dihydro-1,4- benzoxazepin-4(5H)-yl]-N,N-dimethylazetidine-1- sulfonamide Me H

CN Cl 48 Peak 1 (Ex. 105) Peak 2 (Ex. 106)  107,  108 9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-4-(cyanomethyl)-2- methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6- carbonitrile Me H

CN Cl 59 Peak 1 (Ex. 107) Peak 2 (Ex. 108)  109,  110 2-[9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl- 2,3-dihydro-1,4- benzoxazepin-4(5H)-yl]acetamide Me H

CN Cl 59 Peak 1 (Ex. 109) Peak 2 (Ex. 110)  111,  112 9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-4-(2-methoxyethyl)- 2-methyl-2,3,4,5- tetrahydro-1,4-benzoxazepine-6- carbonitrile Me H

CN Cl 59 Peak 1 (Ex. 111) Peak 2 (Ex. 112)  113,   114,  115 3-[9-[1-(4-amino-3-methyl- 1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl- 2,3-dihydro-1,4- benzoxazepin-4(5H)-yl]-N-methylcyclobutanecarbox- amide Me H

CN Cl 67 Peak 1 (Ex. 113) Peak 2 (Ex. 114) Peak 3 (Ex. 115) ^(a)Compoundmade by an analogous procedure to the indicated Example procedure. Peakinformation indicates the order in which the diasteromers eluted underthe analogous column conditions.

TABLE 2 Ex. MS No. [M + H]⁺ ¹H NMR Spectra 73 503.1 ¹H NMR (300 MHz,DMSO-d₆): δ 8.14 (s, 1 H), 7.31 (m, 1 H), 6.22 (m, 1 H), 4.20 (m, 1 H),3.87 (m, 3 H), 3.60 (m, 6 H), 2.80 (m, 2 H), 2.71 (s, 6 H), 2.54 (s, 3H), 1.69 (m, 3 H) 74 539.2 ¹H NMR (300 MHz, DMSO-d₆): δ 8.12 (s, 1 H),7.35 (m, 1 H), 6.22 (m, 1 H), 3.95 (m, 1 H), 3.77 (m, 2 H), 3.61 (m, 4H), 2.80 (m, 2 H), 2.69 (s, 6 H), 2.55 (s, 3 H), 1.69 (m, 3 H) 75 524.1¹H NMR (300 MHz, CD₃OD): δ 8.12 (s, 1 H), 7.32 (m, 1 H), 6.38 (m, 1 H),3.93 (m, 3 H), 3.80 (m, 3 H), 3.52 (m, 2 H), 2.91 (s, 3 H), 2.61 (s, 3H), 1.79 (m, 3 H), 1.31 (m, 3 H) 76 502.2 ¹H NMR (300 MHz, CD₃OD): δ8.14 (s, 1 H), 7.33 (m, 1 H), 6.39 (m, 1 H), 4.20 (m, 1 H), 3.99 (m, 3H), 3.79 (m, 2 H), 3.60 (m, 1 H), 3.49 (m, 1 H), 2.12 (m, 2 H), 1.78 (m,3 H), 1.31 (m, 3 H), 1.05 (m, 3 H) 77 449.2 78 449.2 79 504.1 80 504.1¹H NMR (300 MHz, DMSO-d₆): δ 8.11 (s, 1 H), 7.39 (m, 1 H), 6.28 (m, 1H), 3.82 (m, 5 H), 3.65 (m, 3 H), 3.50 (s, 3 H), 2.85 (m, 1 H), 2.63 (m,1 H), 2.55 (s, 3 H), 1.66 (m, 3 H), 1.29 (m, 3 H) 81 525.1 82 525.1 ¹HNMR (300 MHz, DMSO-d₆): δ 8.11 (s, 1 H), 7.40 (m, 1 H), 6.85 (s, 2 H),6.28 (m, 1 H), 3.82 (m, 3 H), 3.69 (m, 2 H), 3.52 (m, 3 H), 2.80 (m, 1H), 2.62 (m, 1 H), 2.55 (s, 3 H), 1.67 (m, 3 H), 1.28 (m, 3 H) 83 489.284 489.2 85 504.2 86 504.2 87 503.2 88 503.2 89 495.1 90 517.1^(b) 91524.2 92 511.1 93 531.1 94 531.1 95 509.3 96 509.2 97 524.3 98 524.2 99525.2 100 525.3 101 538.2 102 538.2 103 497.2 104 497.1 105 560.1 106560.1 107 437.1 108 437.2 109 455.2 110 455.1 111 456.2 112 456.1 113509.1 114 509.1 115 509.2 ^(b)[M + Na]

Example A1: PI3K Enzyme Assay

PI3-Kinase luminescent assay kit including lipid kinase substrate,D-myo-phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D(+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked (PIP2),biotinylated I(1,3,4,5)P4, PI(3,4,5)P3 Detector Protein is purchasedfrom Echelon Biosciences (Salt Lake City, Utah). AlphaScreen™ GSTDetection Kit including donor and acceptor beads is purchased fromPerkinElmer Life Sciences (Waltham, Mass.). PI3Kδ (p110δ/p85α) ispurchased from Millipore (Bedford, Mass.). ATP, MgCl₂, DTT, EDTA, HEPESand CHAPS are purchased from Sigma-Aldrich (St. Louis, Mo.).

AlphaScreen™ Assay for PI3Kδ

The kinase reaction are conducted in 384-well REMP plate from ThermoFisher Scientific in a final volume of 40 μL. Inhibitors are firstdiluted serially in DMSO and added to the plate wells before theaddition of other reaction components. The final concentration of DMSOin the assay is 2%. The PI3K assays are carried out at room temperaturein 50 mM HEPES, pH 7.4, 5 mM MgCl₂, 50 mM NaCl, 5 mM DTT and CHAPS0.04%. Reactions are initiated by the addition of ATP, the finalreaction mixture consisted of 20 M PIP2, 20 M ATP, 1.2 nM PI3Kδ areincubated for 20 minutes. 10 μL of reaction mixture are then transferredto 5 μL 50 nM biotinylated I(1,3,4,5)P4 in quench buffer: 50 mM HEPES pH7.4, 150 mM NaCl, 10 mM EDTA, 5 mM DTT, 0.1% Tween-20, followed with theaddition of 10 μL AlphaScreen™ donor and acceptor beads suspended inquench buffer containing 25 nM PI(3,4,5)P3 detector protein. The finalconcentration of both donor and acceptor beads is 20 mg/ml. After platesealing, the plates are incubated in a dark location at room temperaturefor 2 hours. The activity of the product is determined on Fusion-alphamicroplate reader (Perkin-Elmer). IC₅₀ determination is performed byfitting the curve of percent control activity versus the log of theinhibitor concentration using the GraphPad Prism 3.0 software. Compoundswith an IC₅₀ of less than 10 μM in the assay of Example A1 areconsidered to be active.

Example A2: PI3K Enzyme Assay

Materials:

Lipid kinase substrate, phosphoinositol-4,5-bisphosphate (PIP2), arepurchased from Echelon Biosciences (Salt Lake City, Utah). PI3K isoformsα, β, δ and γ are purchased from Millipore (Bedford, Mass.). ATP, MgCl₂,DTT, EDTA, MOPS and CHAPS are purchased from Sigma-Aldrich (St. Louis,Mo.).

The kinase reaction are conducted in clear-bottom 96-well plate fromThermo Fisher Scientific in a final volume of 24 μL. Inhibitors arefirst diluted serially in DMSO and added to the plate wells before theaddition of other reaction components. The final concentration of DMSOin the assay is 0.5%. The PI3K assays are carried out at roomtemperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mM DTT and CHAPS0.03%. The reaction mixture is prepared containing 50 M PIP2, kinase andvarying concentration of inhibitors. Reactions are initiated by theaddition of ATP containing 2.2 μCi [γ-³³P]ATP to a final concentrationof 1000 μM. The final concentration of PI3K isoforms α, β, δ and γ inthe assay were 1.3, 9.4, 2.9 and 10.8 nM, respectively. Reactions areincubated for 180 minutes and terminated by the addition of 100 μL of 1M potassium phosphate pH 8.0, 30 mM EDTA quench buffer. A 100 μL aliquotof the reaction solution are then transferred to 96-well MilliporeMultiScreen IP 0.45 m PVDF filter plate (The filter plate is prewettedwith 200 μL 100% ethanol, distilled water, and 1 M potassium phosphatepH 8.0, respectively). The filter plate is aspirated on a MilliporeManifold under vacuum and washed with 18×200 μL wash buffer containing 1M potassium phosphate pH 8.0 and 1 mM ATP. After drying by aspirationand blotting, the plate is air dried in an incubator at 37° C.overnight. Packard TopCount adapter (Millipore) is then attached to theplate followed with addition of 120 μL Microscint 20 scintillationcocktail (Perkin Elmer) in each well. After the plate sealing, theradioactivity of the product is determined by scintillation counting onTopcount (Perkin-Elmer). IC₅₀ determination is performed by fitting thecurve of percent control activity versus the log of the inhibitorconcentration using the GraphPad Prism 3.0 software. Compounds with anIC₅₀ of less than 10 μM in the assay of Example A2 are considered to beactive.

Example A3: PI3Kδ Scintillation Proximity Assay

Materials

[γ-³³P]ATP (10 mCi/mL) was purchased from Perkin-Elmer (Waltham, Mass.).Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate(PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked(PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (SaltLake City, Utah). PI3Kδ (p110δ/p85α) was purchased from Millipore(Bedford, Mass.). ATP, MgCl₂, DTT, EDTA, MOPS and CHAPS were purchasedfrom Sigma-Aldrich (St. Louis, Mo.). Wheat Germ Agglutinin (WGA) YSi SPAScintillation Beads was purchased from GE healthcare life sciences(Piscataway, N.J.).

The kinase reaction was conducted in polystyrene 384-well matrix whiteplate from Thermo Fisher Scientific in a final volume of 25 μL.Inhibitors were first diluted serially in DMSO and added to the platewells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 0.5%. The PI3K assays werecarried out at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mMDTT and CHAPS 0.03%. Reactions were initiated by the addition of ATP,the final reaction mixture consisted of 20 M PIP2, 20 M ATP, 0.2 μCi[γ-³³P]ATP, 4 nM PI3Kδ. Reactions were incubated for 210 min andterminated by the addition of 40 μL SPA beads suspended in quenchbuffer: 150 mM potassium phosphate pH 8.0, 20% glycerol. 25 mM EDTA, 400M ATP. The final concentration of SPA beads was 1.0 mg/mL. After theplate sealing, plates were shaken overnight at room temperature andcentrifuged at 1800 rpm for 10 minutes, the radioactivity of the productwas determined by scintillation counting on Topcount (Perkin-Elmer).IC₅₀ determination was performed by fitting the curve of percent controlactivity versus the log of the inhibitor concentration using theGraphPad Prism 3.0 software. Compounds with an IC₅₀ of less than 10 μMin the assay of Example A3 are considered to be active. IC₅₀ data forExamples 1-25 is presented in Table 3 for PI3Kδ as determined by theassay of Example A2 or A3 as indicated

TABLE 3 Example # PI3Kδ IC₅₀ (nM)* Assay 1 ++ A3 2 + A3 3 + A3 4 + A35 + A3 6 + A3 7 + A3 8 + A3 9 + A3 10 + A3 11 + A3 12 + A3 13 + A3 14 +A3 15 + A3 16 + A3 17 + A3 18 + A3 19 + A3 20 + A3 21 + A3 22 + A3 23 +A3 24 + A3 25 + A3 26 + A2 27 + A2 28 + A2 29 + A2 30 + A2 31 +++++ A232 + A2 33 ++ A2 34 + A2 35 + A2 36 +++ A2 37 + A2 38 +++++ A2 39 +++++A2 40 + A2 41 + A2 42 + A2 43 + A2 44 + A2 45 + A2 46 + A2 47 + A2 48 ++A2 49 + A2 50 + A2 51 + A2 52 + A2 53 + A2 54 + A2 55 + A2 56 + A2 57 +A2 58 + A2 59 + A2 60 + A2 61 +++++ A2 62 + A2 63 + A2 64 ++ A2 65 + A266 + A2 67 + A2 68 + A2 69 + A2 70 + A2 72 ++ A2 73 + A2 74 + A2 75 + A276 + A2 77 + A2 78 + A2 79 + A2 80 + A2 81 + A2 82 + A2 83 + A2 84 + A285 + A2 86 + A2 87 ++ A2 88 + A2 89 + A2 90 + A2 91 + A2 92 + A2 93 + A294 + A2 95 + A2 96 + A2 97 + A2 98 + A2 99 + A2 100 + A2 101 + A2 102 +A2 103 + A2 104 + A2 105 + A2 106 + A2 107 + A2 108 + A2 109 + A2 110 +A2 111 + A2 112 + A2 113 + A2 114 + A2 115 + A2 *column symbols: +refers to ≤100 nM, ++ refers to >100 nM to 500 nM, +++ refers to >500 nMto 1000 nM, ++++ refers to >1000 nM to 10,000 nM, ++++ refers to >800 nM

Example B1: B Cell Proliferation Assay

To acquire B cells, human PBMC are isolated from the peripheral blood ofnormal, drug free donors by standard density gradient centrifugation onFicoll-Hypague (GE Healthcare, Piscataway, N.J.) and incubated withanti-CD19 microbeads (Miltenyi Biotech, Auburn, Calif.). The B cells arethen purified by positive immunosorting using an autoMacs (MiltenyiBiotech) according to the manufacture's instruction.

The purified B cells (2×10⁵/well/200 μL) are cultured in 96-wellultra-low binding plates (Corning, Corning, N.Y.) in RPMI1640, 10% FBSand goat F(ab′)2 anti-human IgM (10 g/ml) (Invitrogen, Carlsbad, Calif.)in the presence of different amount of test compounds for three days.[³H]-thymidine (1 μCi/well) (PerkinElmer, Boston, Mass.) in PBS is thenadded to the B cell cultures for an additional 12 hours before theincorporated radioactivity is separated by filtration with water throughGF/B filters (Packard Bioscience, Meriden, Conn.) and measured by liquidscintillation counting with a TopCount (Packard Bioscience). Compoundswith an IC₅₀ of less than 10 μM in the assay of Example B1 areconsidered to be active.

Example B2: Pfeiffer Cell Proliferation Assay

Pfeiffer cell line (diffuse large B cell lymphoma) are purchased fromATCC (Manassas, Va.) and maintained in the culture medium recommended(RPMI and 10% FBS). To measure the anti-proliferation activity of thecompounds, the Pfeiffer cells are plated with the culture medium (2×10³cells/well/per 200 μl) into 96-well ultra-low binding plates (Corning,Corning, N.Y.), in the presence or absence of a concentration range oftest compounds. After 3-4 days, [³H]-thymidine (1 μCi/well)(PerkinElmer, Boston, Mass.) in PBS is then added to the cell culturefor an additional 12 hours before the incorporated radioactivity isseparated by filtration with water through GF/B filters (PackardBioscience, Meridenj, Conn.) and measured by liquid scintillationcounting with a TopCount (Packard Bioscience). Compounds with an IC₅₀ ofless than 10 μM in the assay of Example B2 are considered to be active.

Example B3: SUDHL-6 Cell Proliferation Assay

SUDHL-6 cell line (diffuse large B cell lymphoma) was purchased fromATCC (Manassas, Va.) and maintained in the culture medium recommended(RPMI and 10% FBS). To measure the anti-proliferation activity of thecompounds through ATP quantitation, the SUDHL-6 cells was plated withthe culture medium (5000 cells/well/per 200 μl) into 96-well polystyreneclear black tissue culture plate (Greiner-bio-one through VWR, NJ) inthe presence or absence of a concentration range of test compounds.After 3 days, Cell Titer-GLO Luminescent (Promega, Madison, Wis.) cellculture agent was added to each well for 10 minutes at room temperatureto stabilize the luminescent signal. This determines the number ofviable cells in culture based on quantitation of the ATP present, whichsignals the presence of metabolically active cells. Luminescence wasmeasured with the TopCount 384 (Packard Bioscience through Perkin Elmer,Boston, Mass.). Compounds with an IC₅₀ of less than 10 μM in in theassay of Example B3 are considered to be active. IC₅₀ data for theExamples is presented in Table 4 determined by the assay of Example B3.

TABLE 4 Example # SUDHL IC₅₀ (nM)* 3 + 4 + 5 + 6 + 10 + 12 + 13 + 18 ++20 + 21 + 23 + 24 ++ 26 + 27 + 28 + 29 + 30 + 32 + 34 + 35 + 37 + 40 +41 + 42 + 44 + 45 + 46 + 47 + 48 ++ 49 + 50 + 51 + 53 + 54 + 55 + 56 +57 + 58 + 60 + 62 + 63 + 65 + 66 + 67 + 68 + 69 + 70 + 71 ++ 73 + 74 ++75 + 76 + 78 + 80 + 82 + 83 + 84 + 85 + 86 + 88 + 89 + 90 + 91 + 92 +93 + 94 + 95 + 96 + 97 + 98 + 99 + 100 + 101 + 102 + 104 + 105 + 106 +108 + 110 + 112 + 114 + 115 + *column symbols: + refers to ≤500 nM, ++refers to >500 nM to 1000 nM, +++ refers to >1000 nM to 2000 nM, ++++refers to >2000 nM to 10,000 nM

Example C: Akt Phosphorylation Assay

Ramos cells (B lymphocyte from Burkitts lymphoma) are obtained from ATCC(Manassas, Va.) and maintained in RPMI1640 and 10% FBS. The cells (3×10⁷cells/tube/3 mL in RPMI) are incubated with different amounts of testcompounds for 2 hrs at 37° C. and then stimulated with goat F(ab′)2anti-human IgM (5 μg/mL) (Invitrogen) for 17 minutes in a 37° C. waterbath. The stimulated cells are spun down at 4° C. with centrifugationand whole cell extracts are prepared using 300 μL lysis buffer (CellSignaling Technology, Danvers, Mass.). The resulting lysates aresonicated and supernatants are collected. The phosphorylation level ofAkt in the supernatants are analyzed by using PathScan phospho-Akt1(Ser473) sandwich ELISA kits (Cell Signaling Technology) according tothe manufacturer's instruction.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula IVb:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is methyl; R⁴is methyl, F or CN; R⁵ is Cl; R⁶ is H; R^(3b) is H, Cy, —(C₁₋₃alkylene)-Cy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(═O)R^(b), C(═O)NR^(c)R^(d),C(═O)OR^(a), or S(═O)₂R^(b), wherein said C₁₋₆ alkyl is optionallysubstituted by 1, 2, 3, or 4 independently selected R^(13b) groups; eachR^(a), R^(b), R^(c), and R^(d) is independently selected from C₁₋₆ alkyland Cy; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or3 independently selected R^(13b) groups; each Cy is independentlyselected from monocyclic C₃₋₇ cycloalkyl, monocyclic 4-7 memberedheterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl,wherein said monocyclic C₃₋₇ cycloalkyl, monocyclic 4-7 memberedheterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl areoptionally substituted with 1, 2, 3, or 4 independently selected R^(13b)groups; each R^(13b) is independently selected from CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),NR^(c1)C(═O)R^(b1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl is optionally substituted with 1 or 2 independently selectedR¹¹ groups; each R¹¹ is independently selected from OH and carbamyl;each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and each R^(b1) is independently selectedfrom C₁₋₆ alkyl and C₁₋₆ haloalkyl.
 2. The compound of claim 1, whereinR^(3b) is H.
 3. The compound of claim 1, wherein R⁴ is methyl.
 4. Thecompound of claim 1, wherein the compound is9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one,or a pharmaceutically acceptable salt thereof.
 5. A compound of FormulaXXIV:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is methyl;R^(3a) is methyl; R⁴ is methyl, F or CN; R⁵ is Cl; R⁶ is H; R^(3b) is H,Cy, —(C₁₋₃ alkylene)-Cy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), or S(═O)₂R^(b), wherein said C₁₋₆ alkylis optionally substituted by 1, 2, 3, or 4 independently selectedR^(13b) groups; each R^(a), R^(b), R^(c), and R^(d) is independentlyselected from C₁₋₆ alkyl and Cy; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R^(13b) groups; eachCy is independently selected from monocyclic C₃₋₇ cycloalkyl, monocyclic4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 memberedheteroaryl, wherein said monocyclic C₃₋₇ cycloalkyl, monocyclic 4-7membered heterocycloalkyl, phenyl, and monocyclic 5-6 memberedheteroaryl are optionally substituted with 1, 2, 3, or 4 independentlyselected R^(13b) groups; each R^(13b) is independently selected from CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1),C(═O)OR^(a1), NR^(c1)C(═O)R^(b1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2independently selected R¹¹ groups; each R¹¹ is independently selectedfrom OH and carbamyl; each R^(a1), R^(c1), and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and each R^(b1) isindependently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl.
 6. Thecompound of claim 5, wherein R^(3b) is Cy.
 7. The compound of claim 5,wherein R⁴ is methyl.
 8. The compound of claim 5, wherein the compoundis4-(1-Acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-4,5-dihydro-1,4-benzoxazepin-3(2H)-one,or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.
 10. A pharmaceutical composition comprising a compound of claim5, or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 11. A method of treating B celllymphoma in a patient, comprising administering to said patient atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 12. A method of treatingdiffuse large B cell lymphoma in a patient, comprising administering tosaid patient a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof.
 13. A method oftreating chronic lymphocytic leukemia in a patient, comprisingadministering to said patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 14.A method of treating follicular B-cell Non-Hodgkin lymphoma in apatient, comprising administering to said patient a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 15. A method of treating small lymphocyticlymphoma in a patient, comprising administering to said patient atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 16. A method of treatingNon-Hodgkin lymphoma in a patient, comprising administering to saidpatient a therapeutically effective amount of a compound of claim 1, ora pharmaceutically acceptable salt thereof.
 17. A method of treating Bcell lymphoma in a patient, comprising administering to said patient atherapeutically effective amount of a compound of claim 5, or apharmaceutically acceptable salt thereof.
 18. A method of treatingdiffuse large B cell lymphoma in a patient, comprising administering tosaid patient a therapeutically effective amount of a compound of claim5, or a pharmaceutically acceptable salt thereof.
 19. A method oftreating chronic lymphocytic leukemia in a patient, comprisingadministering to said patient a therapeutically effective amount of acompound of claim 5, or a pharmaceutically acceptable salt thereof. 20.A method of treating follicular B-cell Non-Hodgkin lymphoma in apatient, comprising administering to said patient a therapeuticallyeffective amount of a compound of claim 5, or a pharmaceuticallyacceptable salt thereof.
 21. A method of treating small lymphocyticlymphoma in a patient, comprising administering to said patient atherapeutically effective amount of a compound of claim 5, or apharmaceutically acceptable salt thereof.
 22. A method of treatingNon-Hodgkin lymphoma in a patient, comprising administering to saidpatient a therapeutically effective amount of a compound of claim 5, ora pharmaceutically acceptable salt thereof.